CRS Newsletter. Volume 25, Number 2. 2008

.
Newsletter
A publication of the Controlled Release Society
Volume 25 • Number 2 • 2008
What’s Inside
Formulating Paediatric
Medicines
Encapsulation of
Probiotics with Alginates
Interspecies Differences
and Formulation
Absorption
Tissue and Cell Culture
Basics
35th CRS Annual
Meeting & Exhibition
Transdermal Patents
SGW-2431 DDT 8.125x10.875
8/25/06
4:33 PM
Page 1
Check out the latest online issue of Drug Delivery Technology at
www.drugdeliverytech.com
Introducing
Drug Delivery Technology...online!
• No special software required
• Table of contents navigation
• Click through to advertisers’ sites and content
• Print, send, and share articles with colleagues
• Interactive correspondence with editors and advertisers
• Content searchable by keywords
• Faster online distribution
Newsletter
Vol. 25 • No. 2 • 2008
Steven Giannos
Editor
Table of Contents
From the Editors ......................................................................................................... 2
From the President ..................................................................................................... 3
Bozena Michniak-Kohn
Editor
Spotlight
Paediatric Medicines: Formulating a Solution .................................................................... 4
Consumer & Diversified Products
Encapsulation of Probiotics in Alginate Systems ................................................................ 7
From the Vet Group
Interspecies Differences Influencing Interspecies Extrapolations Part II of III:
Interspecies Differences Influencing the Absorption of Oral and Parenteral Formulations ... 10
From the Education Committee
Back to the Basics: 1. Tissue and Cell Culture ................................................................. 12
Yvonne Perrie
Editor
Rod Walker
Editor
Chapter News
8th International Symposium on NDDS Organised by CRS Indian Chapter .....................
2007 Meeting of the CRS Italian Chapter . .....................................................................
New Zealand Chapter of CRS Holds 10th Formulation and Drug Delivery
Conference in Dunedin .................................................................................................
CRS Nordic Chapter Annual Meeting to Be Held in Tromsø, Norway ..............................
UKICRS Conference Review: 14th Annual Symposium 2008 Predicting
Drug Delivery—Opportunities and Challenges ...............................................................
15
15
16
18
18
35th CRS Annual Meeting & Exposition
Why You Absolutely Have to Be There ........................................................................... 20
See These Exhibitors at the 35th CRS Annual Meeting & Exposition ................................. 21
What’s on Board?
What’s on Board for the Future? .................................................................................... 22
Patent Watch
Transdermal Update 2008 . ............................................................................................ 23
People in the News . ................................................................................................ 28
Jamileh Lakkis
Editorial Board
Welcome New Members ......................................................................................... 30
In the News .............................................................................................................. 31
Event Calendar . ................................................................................................ Cover 4
Advertiser’s Index
Arlene McDowell
Editorial Board
Drug Delivery Technology ................................................................................ Cover 2
CMA/Microdialysis .................................................................................................... 27
Elsevier ........................................................................................................................ 6
OctoPlus .................................................................................................................... 22
1
From the Editor
Editors
Yvonne Perrie
Aston University, School of Life and Health Sciences
Aston Triangle, Birmingham, U.K.
Steven Giannos
Bozena Michniak-Kohn
Yvonne Perrie
Rod Walker
Editorial Board
Jamileh Lakkis (C&DP)
Arlene McDowell (Vet Group)
Publications Committee Chair
Ijeoma Uchegbu
The CRS Newsletter is the official
newsletter of the Controlled Release
Society. The newsletter is published four
times annually providing scientific and
technical information pertinent to the
controlled release community and news
about society and chapter activities.
Members receive the newsletter via mail.
The newsletter may also be viewed online
at www.controlledreleasesociety.org.
Newsletter articles reflect only the views
of the authors. Publication of articles or
advertisements within the CRS Newsletter
does not constitute endorsement by the
Controlled Release Society or its agents
of products, services, or views expressed
herein. No representation is made as to
the accuracy hereof and the publication is
printed subject to errors and omissions.
Editorial contributions should be
directed to the CRS Newsletter Editors,
([email protected]) and are
subject to the terms and conditions of
the Editorial and Publication Release.
Publisher assumes no responsibility for the
safety or return of artwork, photographs,
or manuscripts.
Requests for advertisement placement may
be directed to Debby Woodard, Business
Development Department; telephone
+1.651.994.3817, or e-mail at dwoodard@
scisoc.org. All advertisements are subject
to “General Conditions of Sale.”
Colonic Irrigation or Irritation: It Is All in the Title
M
any of you will be reading this around or perhaps at the CRS Annual Meeting
& Exposition, where this year we have had a bumper number of abstracts
submitted. With so much research to review, how do we grab each others’ attention
and get our own research noticed? Indeed, in the new wave of measuring research by
metrics, it is of vital importance that we get our papers noticed. So, how do we do it?
One of the most important decisions is the title of the presentation.
It is often suggested that titles be limited to fewer than 10 words, not as a result of
limited space but rather limited attention span. An article by Palladino and
Handelsman (1) provides examples of “routine old boring titles.” I dare not quote
their examples as they are much too similar to many of my own titles. In a bid to
create more exciting titles, they suggest using a colon. In defence of this strategy, they
reference Dillon (2), who found that a colon was used in 72% of article titles and was
associated with publishability, complexity of thought, and distinction of endeavour.
This is a lot just from a colon! Others are also suggesting this strategy. In a recent
column (3), James Hartley (Keele University, UK), suggests colons could be an
imaginative way to improve citation counts and reports some interesting facts: the
use of colonic titles in research papers is increasing; those working in the arts and
social sciences like their colons (in titles); and within the science disciplines we also
have different preferences for the use of colons, with single authors using colons more
often than groups of authors.
The use of colons in a title has some key advantages. Clear punctuation and compound
constructs in titles can provide immediate visual impact. By splitting the sentence into
two sections, we can provide the primary information about the content more easily.
Therefore, we can have text that attracts (e.g., “Colonic Interjection”) followed by text
that informs (“A Study of the CRS Poster Titles”). Palladino and Handelsman (2) also
suggest we pose questions in titles, e.g., “Hair: Does It Matter?”—clearly this is short,
snappy, to the point, and controversial with some.
Controlled Release Society
3340 Pilot Knob Road
St. Paul, MN 55121 U.S.A.
However, not everyone likes colons in titles; some even accuse colons of being a
fashion statement and demand their use be stopped. Indeed, I myself have fallen
victim to such colonic purging. I recently was requested to irrigate the colon from the
title of one of my CRS abstracts. The reviewer was very polite with the request, so we
were happy to oblige. However, on further investigation into this topic—which
appears a hotter debate than one might first think—I have decided to become colon
retentive and continue to adopt a compound construction for titles. As you review the
posters at the CRS meeting, note have many people have used a colon.
Telephone: +1.651.454.7250
Facsimile: +1.651.454.0766
Best wishes and enjoy the meeting!
Unauthorized reproduction in whole or in
part is prohibited. Requests for permission
should be directed to the Editors at
[email protected].
©Copyright 2008 Controlled Release
Society. All rights reserved.
Visit www.controlledreleasesociety.org or
e-mail [email protected] on questions about
membership, meetings, publications, and
services.
Contact [email protected] for
information about exhibiting, advertising
or other visibility opportunities.
2
Yvonne Perrie
References
1. Palladino, JJ, Handelsman, MM. Creating titles for presentations: Beyond the colon,
Published online at Denverhttp://www.psichi.org/pubs/articles/article_134.asp (1998).
(Accessed June 5, 2008).
2. Dillon, JT. The emergence of the colon: An empirical correlate of scholarship, Am. Psychol.
36: 879-884 (1981).
3. Hartley, J. Colonic information. Times Higher Education, Feb. 28, p 26 (2008). n
From the President
Susan Cady
Intervet/Schering-Plough Animal Health, Yardley, PA U.S.A.
O
ver the past year the CRS Board of Directors has developed
a new CRS strategic plan that specifies goals and objectives,
along with current priorities for achieving these objectives. I
would like to highlight some of our activities and the progress
that has been made on some of the strategic initiatives that have
grown out of these discussions:
Offering more satellite meetings is one of the key initiatives
under Goal I—Promote high quality research in the science of
delivery of bioactives. Two satellite meetings are planned for
2008, and the subcommittee is hard at work developing them.
The first satellite meeting of 2008, “Multi-particulate Drug
Delivery Systems: Challenges and Scope,” was held in April in
Orlando, FL. A special thanks to Chairs Ali R. RajabiSiahboomi, Colorcon, Inc., and Gurvinder Singh Rekhi, Elan
Drug Technologies, who organized this successful meeting. The
2-day program featured presenters from 5 countries and
attracted 70 attendees. The second satellite meeting of 2008,
“Critical Variables in the In Vitro and In Vivo Performance of
Parenteral Sustained Release Products” will be held in
conjunction with the AAPS Annual Meeting on Saturday and
Sunday, November 15–16, at the Georgia World Congress
Center in Atlanta, GA.
Evaluating the feasibility of creating a CRS publications
program is a key initiative under Goal III—Become the primary
year-round information resource for the science of delivery of
bioactives. In May, a meeting was held at CRS headquarters in
St. Paul, MN, with the objective of defining the goals and
objectives of the book publishing subsection of the initiative.
Mike Rathbone has accepted the responsibility of chairing this
important program. He is working with his advisory board on
some new titles that will establish CRS books as quality musthaves for our members. Hopefully, they will also be seen as
important works that the overall scientific community needs for
its library collections. We know that it will take some time for
editors and authors to write their chapters, but over the next 30
months we will watch their progress, and I look forward to
seeing these in print and adding them to my reference collection.
Hopefully, you will as well. If you have suggestions and ideas,
please contact Jody Grider at CRS headquarters (E-mail:
[email protected]; Tel: +1.651.994.3862).
Please take the time to look at the strategic plan in more detail
on the website (www.controlledreleasesociety.org/about). There
are many other activities currently underway, such as the
Foundation scholarship program and the mentoring program.
As you review the strategic plan, are there initiatives you are
interested in contributing to? Are there programs that you can
contribute to and help the society, or some one who you can
recommend? Please let me know, and I will get you the
appropriate contact information. CRS needs and relies on its
member volunteers to advance its efforts—please become one
and see how your efforts can help make a difference to our
society.
There are so many volunteers within our society who contribute
to the various committee efforts. If there is a committee or
initiative that you would like to learn more about or would like
to participate in, please contact the committee chair or a CRS
staff member to express your interest. The redesigned CRS
website should be up and running before our annual meeting.
Take a look and see if there is a committee in which you would
like to participate.
As the staff and planning committees finalize the logistics for the
35th Annual Meeting & Exposition of the CRS in New York
City, I hope that you plan to join us and actively contribute to
the discussions and networking that make our meetings a special
place to share experiences and learn about other areas within the
delivery of bioactives. The networking, exhibitor interaction, and
scientific exchanges might just contribute to that new project you
are contemplating.
Looking forward to seeing you at the 35th annual meeting in
New York City!
Susan Cady n
3
Spotlight
Paediatric Medicines: Formulating a Solution
Dr. Daniel Kirby
Medicines for Children Research Fellow
Aston University, Birmingham, U.K.
The formulation of safe, effective, well-tolerated children’s
medicines poses a significant challenge to the pharmaceutical
scientific community, since in addition to the usual problems of
formulation (e.g. solubility and chemical stability of the active),
there exists a plethora of further difficulties involved in
producing a “child-friendly” medicine.
necessitate studies, in order that, in the future, children will
receive medicines that are both safe and acceptable. To make
such studies worthwhile, there are financial incentives in terms of
extensions to existing patents, whilst also recognising the need
for research into off-patent medicines through the offer of
market exclusivity for a specific paediatric formulation of a drug.
For example, although solid oral dosage forms may be perfectly
acceptable for the majority of adult patients, tablets or capsules
may be inappropriate for children, particularly the very young;
thus, alternative formulations are often required. In addition,
taste is a greater determinant of whether the desired dose can be
effectively delivered and also of medication compliance and,
hence, therapeutic outcome for children (3). Indeed, recent
results suggest that healthcare professionals—who encounter
formulation issues on a daily basis—identify palatability as the
greatest problem when administering children’s medicines (Fig.
1; Kirby et al., unpublished data).
As part of the drive to improve the current situation, several
initiatives have been set up to facilitate the growing demand for
clinical research in the paediatric setting. Indeed, the World
Health Organisation has recently launched a global campaign to
“make medicines child size,” and several member states in
Europe have launched programmes to support further research
in this field. One such venture is the UK Medicines for Children
Research Network (UK MCRN), which incorporates a work
stream—in collaboration with three UK academic centres—to
focus specifically on the formulation aspects of children’s
medicines.
Added to this the varying pharmacokinetics of what is a
heterogeneous population (it is often stated that children are not
small adults [6], rendering extrapolation from adult data
unsuitable), the problems associated with clinical trials (e.g.
recruitment, available numbers, expense, ethics), and the financial
viability of producing medicines specific to a small percentage of
the market (≈15%), it is no surprise that there exists a severe lack
of paediatric-specific formulations currently available.
An area of particular concern is that of extemporaneous
dispensing. Defined as the process of compounding of
ingredients to prepare a medicine for an individual patient (5),
the tendency in paediatrics is to convert a solid oral dosage form
into a liquid oral dosage form through, for example, the crushing
Consequently, the use of medicines in an “off-label” (i.e. outside
the terms of the marketing authorisation) or “unlicensed” (i.e. no
license exists at all) manner is widespread, ranging from around
10% in primary care up to 90% in neonatal intensive care units
(1,4). This practice, although necessary, effectively exposes
paediatric patients, generally considered a more vulnerable
population, to an increased risk of adverse events.
As such, paediatrics represents a neglected patient population,
both in terms of clinical efficacy and safety data, as well as the
availability of medical advances, including controlled release
technologies.
In an attempt to tackle this critical issue, FDA (2002 Best
Pharmaceuticals for Children Act) and, more recently, European
(Regulation (EC) No 1901/2006) legislation has been
implemented to encourage and (more so in the European case)
4
Figure 1. Problems associated with children’s medicines, as perceived by U.K.
healthcare professionals. Self-completion questionnaires addressing possible
formulation problems were distributed to paediatric healthcare professionals
from hospitals within the West Midlands and Trent regions of the United
Kingdom. The majority of responses were from nursing staff.
(SEDDS), and microemulsions, amongst others. Moreover,
besides the oral route, there are distinct advantages in using, for
example, suppositories that would negate the issues of taste,
although they may pose problems with acceptability and
compliance.
of tablets followed by dispersion in a suspending agent. Although
this may result in a more acceptable preparation for
administration to a child and, as such, remains an essential part
of paediatric therapy, there are several related risks. For example,
halving of tablets, even when using commercially available tablet
cutters, can lead to between 50 and 150% of the desired dose (2).
In addition, the resulting formulations are rarely characterised
for their pharmaceutical quality. For instance, shelf lives are often
arbitrary figures defined with little or no evidence to support the
physical, chemical, or microbiological stability of the
preparations, whereas the crude suspensions invariably
formulated may inhibit bioavailability or lack dosage uniformity,
thus leading to potential under- or overdosing. In addition, the
excipients employed in order to act, for example, as preservatives
or to enhance organoleptic properties—notably ethanol, benzyl
alcohols, and certain flavourings and sweeteners—may also pose
potentially fatal toxicity and health-related risks, particularly in
the very young. Additionally, problems concerning the
availability of such preparations when transferring from
secondary to primary care (7) further confirms that there is an
evident and urgent need for further research within this field.
It seems obvious then that alternative, age-appropriate
formulations are a research necessity. Indeed, paediatric
medicines offer an opportunity to exploit existing and emerging
technologies, particularly with regard to controlled release. For
example, microencapsulation may be employed in taste-masking
of a poorly tasting pharmaceutical active through, for instance,
the production of granules or pellets (or micropellets) that may
then be coated with a functional polymer (e.g. Eudragit®). A
recent example of the use of such technology, incorporated into a
novel device for paediatric use, is Grünenthal’s Sip®-Technology
for the delivery of antibiotics through a drinking straw.
In addition, the use of particulate delivery systems, such as
liposomes, microspheres, or cyclodextrin complexes, have the
potential to be utilised to improve the solubility, stability, and
palatability of liquid dosage forms in particular, whilst also
offering the potential for controlled release of the active
ingredient. Further, there are several alternative dosage forms
such as mini-tablets, chewable tablets, melts or oro-dispersable
tablets (ODT), fast-dissolving films, powders for reconstitution,
effervescent tablets, self-emulsifying drug delivery systems
In summary, despite the current lack of available “child-friendly”
formulations, recent directives and initiatives have set the agenda
for improving the safety, efficacy and acceptability of paediatric
medicines, and the onus is now on the scientific community to
develop and exploit existing, emerging, and novel technologies to
achieve the goal of better medicines for children.
References
1. Conroy, S, McIntyre, J, Choonara, I. Unlicensed and off label drug
use in neonates, Arch. Dis. Child Fetal Neonatal Ed. 80: F142-F144
(1999).
2. Cook, TJ, Edwards, S, Gyemah, C, Shah, M, Shah, I, Fox, T.
Variability in tablet fragment weights when splitting unscored
cyclobenzaprine 10 mg tablets, J. Am. Pharm. Assoc. 44: 583-586
(2004).
3. Ernest, TB, Elder, DP, Martini, LG, Roberts, M, Ford, JL.
Developing paediatric medicines: Identifying the needs and
recognizing the challenges, J. Pharm. Pharmacol. 59: 1043-1055
(2007).
4. McIntyre, J, Conroy, S, Avery, A, Corns, H, Choonara, I. Unlicensed
and off label prescribing of drugs in general practice, Arch. Dis.
Child. 83: 498-501 (2000).
5. Nunn, AJ. Making medicines that children can take. Arch. Dis.
Child. 88: 369-371 (2003).
6. Stephenson, T. How children’s responses to drugs differ from adults,
Br. J. Clin. Pharmacol. 59: 670-673 (2005).
7. Wong, IC, Basra, N, Yeung, VW, Cope, J. Supply problems of
unlicensed and off-label medicines after discharge, Arch. Dis. Child.
91: 686-688 (2006). n
5
Journal of Controlled Release
is the official journal of the
Controlled Release Society
Reduced Rates
available for
Members
r
Impact facto
2006: 4.012
,
Reports® 2007
(Journal Citation
c)
ifi
nt
ie
Sc
n
so
published by Thom
Join & Subscribe Today!
Members are eligible for the
reduced-rate subscription of
2008 • USD 141 • Print
2008 • USD 115 • Online
(Please note if members would like both online and print
subscriptions, these must be ordered separately).
Information on the journal can be found at:
www.elsevier.com/locate/jconrel
To subscribe online go to:
www.controlledreleasesociety.org
6
Consumer and Diversified Products
Encapsulation of Probiotics in Alginate Systems
Ming-Ju Chen1 and Kun-Nan Chen2
Introduction
Probiotics can be defined as living microbial supplements that can
improve the balance of intestinal microorganisms (1). Good
probiotic viability and activity are considered essential for
probiotics with maximum functionality. To benefit the consumer,
a suggested minimum level for probiotics in food products is 107
CFU/mL (2) at the time of consumption. A major challenge
associated with the application of probiotic cultures in functional
foods is the retention of viability during processing. Moreover,
since viable and biologically active micro-organisms are usually
required at the target site in the host, it is essential that probiotics
withstand the host’s natural barriers, such as gastric transit.
Encapsulation has been investigated for its ability to provide
protection of probiotic microorganisms in both food products
and the intestinal tract. The selection of different types of coating
materials usually depends on the functional properties of the
microcapsules and coating process used. For dairy and food
applications, probiotic encapsulation in food-grade porous
matrices has been used most widely (3). Calcium alginate is
favored above other supporting materials for encapsulating
probiotics due to its simplicity, non-toxicity, biocompatibility,
and low cost (4). Solubilization of alginate gel by sequestering
calcium ions and releasing entrapped cells within the human
intestines is another advantage. Furthermore, this ionically linked
gel is thermostable over the range of 0 to 100°C. This article
summarizes recent developments in the encapsulation of
probiotics using alginate as a coating material.
Native Alginate
Alginate, a nature polymer, is a linear heteropolysaccharide of dmannuronic and l-guluronic acids extracted from various species
of algae. The functional properties of alginate as a supporting material are strongly associated with the composition and sequence
of l-guluronic and D-mannuronic acids. Divalent cations such as
Ca2+ preferentially bind to the polymer of l-guluronic acid (4).
On addition of sodium alginate solution to a calcium solution,
interfacial polymerization is instantaneous, with precipitation of
calcium alginate in the form of beads, followed by a more gradual
gelation of the interior as calcium ions permeate through the alginate systems. The size of the beads is generally dependent on the
viscosity of the polymer solution, the diameter of the orifice, and
the distance between the outlet and the coagulation solution.
Concentrations of sodium alginate and calcium chloride used to
form the beads vary between 1 and 3% alginate and 0.05 and
Department of Animal Science and Technology, National
Taiwan University, Taipei, Taiwan, R.O.C.
2
Department of Mechanical Engineering, Tung Nan University,
Taipei, Taiwan, R.O.C.
1
1.5M CaCl2 (5–7). However, the use of alginate is limited by its
inferior physical stability in the presence of chelating agents such
as phosphate (8) and anti-gelling cations such as sodium and
magnesium ions (9). The chelating agents share an affinity for
calcium, which destabilizes the gel. Furthermore, a cross-linked
alginate matrix system with a very low pH was reported to
undergo a reduction in alginate molecular weight, causing faster
degradation and release of active ingredients (10).
Treated Alginates Coated with Polycations
Coating alginate beads with polycations such as chitosan and poly
l-lysine has been extensively studied in encapsulated probiotics
(5,7–9,11). Chitosan-coated alginate capsules were produced by
dropping an alginate solution into a mixture of calcium chloride
and a chitosan solution (7). Since chitosan, poly-(2-amino-2deoxy-β-d-glucopyranose), is a positively charged polyamine, this
polymer forms polyelectrolyte complexes with alginate and
produces polyanionic polymer membranes that do not dissolve in
the presence of calcium chelators or anti-gelling agents.
Alginate poly-l-lysine microcapsules can provide good
biocompatibility and have potential wide applications in the food
industry (7). They are obtained by suspending alginate beads in a
poly-l-lysine solution. This poly amino acid has a positive charge
and forms a complex with surface alginate that increases the
strength of microcapsules. Cui et al. (5) studied the bifidobacteria
loaded in alginate poly-l-lysine microparticles and indicated that
poly-l-lysine treatment greatly enhanced the survival of
bifidobacteria during storage at 4°C.
Treated Alginates Coated with Prebiotics
Prebiotics are non-digestible food ingredients that can
beneficially affect the host by selectively stimulating the growth
and/or activity of one or a limited number of bacteria in the
colon (12). Several studies (13,14) have confirmed that
incorporation of prebiotics and calcium alginate as coating
materials provides better protection for probiotics in food
systems and eventually in the intestinal tract, a result of proven
synergy between the probiotics and prebiotics. Chen et al. (14)
incorporated prebiotics as coating materials for probiotic
microencapsulation and demonstrated that the addition of
fructooligosaccharides, isomaltooligosaccharides, and peptides in
the walls of probiotic microcapsules provided improved
protection for active organisms. These probiotic counts remained
at 106–107 CFU/g for microcapsules stored for 1 month and
then subjected to a simulated gastric fluid test and a bile salt test.
Techniques for Probiotic Encapsulation
Spherical alginate beads can be produced using extrusion or
emulsification techniques. Extrusion is the simplest and most
7
common technique used to produce probiotic capsules with
hydrocolloids, especially alginates (4,15). One of the major
advantages of this method is that the viscosity of the fluid does
not limit capsule generation (16). Furthermore, the biological
matter can be treated at a lower temperature. Figure 1 shows the
structure of alginate microcapsules prepared using extrusion. The
microcapsules display spherical shapes, with groups of entrapped
bacteria evident in the internal voids and surrounded by the
matrix.
The emulsion technique has also been successfully used for
encapsulating probiotics. The principle of this technique is based
on the relationship between the discontinuous and continuous
phases. The probiotics are essentially mixed into a solution of
alginate (i.e., the discontinuous phase) and dropped into vegetable
oil (i.e., the continuous phase) containing emulsifier (Tween 80)
and surfactant (sodium lauryl sulfate) to form beads. The latter are
harvested later by filtration. Emulsifiers can break up water and
oil emulsions, thus preventing the spheres from coalescing before
breaking up the emulsion. Surfactants can lower the surface
tension in the coating matrix in order to reduce the size of the
spheres. This technique provides both encapsulated and entrapped
core materials and is easy to scale up for large-scale production.
However, several studies have indicated that this technique may
not be suitable for food products. The residual oil, emulsifier, and
surfactant in the encapsulating material can affect the growth of
live probiotics and interact with food components. In addition,
the residual oil may damage the organoleptic properties and
texture of the food products (17).
Survival of Encapsulated Probiotics
Gastrointestinal Conditions. Successful encapsulation of
probiotics should provide
profound survival of beneficial
bacteria during its passage through
the upper digestive tract to ensure
that beneficial effects occur in the
host intestines (18). Most studies
have proven the advantages of
encapsulating probiotics over free
cells under in vitro gastric
conditions. Chen et al. (19) found
that the death rate of the
probiotics in capsules decreased
proportionally with an increase in
alginate concentration (1–3%),
bead size (1–3 mm), and initial
cell numbers, when encapsulated
B. longum was exposed to
simulated gastric and intestinal
juices. However, Hansen et al. (20)
reported that small beads of <100
µm, compared with free cells, did
not significantly protect probiotics
Figure 1. Scanning electron
in simulated gastric media. The
micrograph of optimized B.
effects of the simulated gastric
bifidum microcapsules. (a) Whole
microcapsule; (b) surface; and (c) fluid test (SGFT) on the outer
structure of microcapsules
cross-section.
8
observed by scanning electron
microscopy (SEM) are shown in
Figure 2. The microparticles
retained their shapes, with smaller
sizes and coarser surfaces after the
SGFT. Hansen et al. (20) also
found that the alginate
microspheres retained their shapes
and had smoother surfaces during
exposure to simulated gastric juice
at pH 2.0. A possible explanation
for this observation is that treating
the microparticles with a solution
at pH 2 may cause some calcium
to be displaced. After this
treatment, surface calcium ions
could not contribute anymore to
the stability of the beads, resulting
in smaller beads and smoother
surfaces.
Figure 2. Effects of SGFT on
the outer structure of
microcapsules observed by SEM.
(a) Whole microcapsule; and (b)
surface.
Dairy Products. Encapsulation has been investigated for its
ability to improve the viability of beneficial microorganisms in
dairy products. Sheu et al. (21) studied the survival of culture
bacteria in frozen desserts and
indicated that the survival rate for L.
bulgaricus in continuously frozen ice
milk was approximated at 90%
without a measurable effect on
sensory characteristics when it was
entrapped in calcium alginate. Kebary
et al. (22) also reported that
encapsulating Bifidobacterium spp. in
alginate beads significantly improved
its survival in frozen ice milk
throughout the study’s storage period.
These findings encouraged further
investigations on the incorporation of
encapsulated probiotics in frozen
desserts.
During the yogurt post-acidification
stage (i.e., decrease in pH after
fermentation) and storage at
refrigerated temperatures, major cell
death of probiotic bacteria routinely is
experienced. Incorporating calciumalginate beads into set yogurt
formulations has been shown to
provide better survival over an 8-week
storage period compared with the
survival of free cell counterparts
(23,24). Desmond et al. (25) reported
the viabilities and survival of both
encapsulated Bifidobacterium spp. and
L. paracasei in cheese for at least 6 and
3 months, respectively. In addition,
acetic acid, a common metabolite of
Figure 3. Scanning electron
micrograph showing the
effect of the number of
consecutive cultivations on
microencapsulated probiotics.
(a) Whole microcapsule; (b)
surface; and (c) cross-section.
Bifidobacterium spp. that is not preferred in dairy products, was
not detected during ripening.
The following summarizes two major areas of applications of
encapsulated probiotics in dairy products.
Continuous Cultivation
Alginate microcapsules, by virtue of their high degree of porosity,
allow fast and easy diffusion of materials in and out of the
alginate matrix. This is an advantage for the immobilization of
live cells. Microbiological changes in alginate beads during
consecutive cultivation showed a significant increase in cell counts
(107–1012 CFU/g). SEM observations revealed that after 28 batch
cultivations, the microparticles retained their shapes and surface
morphology, with the probiotic bacteria distributed between the
surfaces and interior of the microcapsules (Figure 3). These
microcapsules produced by alginate offered a very high cellretention capacity for microorganisms, even in the inner pores of
the matrix. Growth and aggregation of cells in the voids resulted
in complete filling of the outer and inner pores of the
microparticles. An increase in cell counts with an increasing
number of cultivations for fermented milk was also observed.
Immediately after the addition of microcapsules to milk, the
probiotics reached a concentration of 104 CFU/mL. This
indicated that part of the microflora contained in the capsule was
transferred to the milk. In a Kefir system, however, using
encapsulated “kefir” cultures as the initial inoculum resulted in a
lag period before the fermented milk reached normal cell
population. It should be noted here that it is important to activate
the encapsulated starter cultures before using them for cultivation.
Incorporation into Dairy Products
In the dairy industry, encapsulated probiotics can be used to
accelerate cheese ripening, improve probiotic survival, and
enhance their storage stability. Many dairy culture companies can
design and manufacture, according to the customers’ requests,
microencapsulated ingredients that can synergistically provide
benefits in the areas of nutrition, digestion, and immunity.
Examples of such applications include yogurt, both set and
stirred types, as well as cheese.
References
1. Fuller, R. Probiotics: The Scientific Basis, Chapman & Hall,
London, p125 (1992).
2. Kurman, JA, Rasic, JL. The health potential of products containing
bifidobacteria. In, Robinson, RK (ed.), Therapeutic Properties of
Fermented Milk, Elsevier Application Food Science Series,
Elsevier, London, pp115-117 (1991).
3. Champagne, CP, Gaudy, C, Poncelet, D, Neufeld, RJ. Lactococcus
lactis release from calcium alginate beads, Appl. Environ. Microb.
58: 1429-1434 (1992).
4. Krasaekoopt, W, Bhandari, B, Deeth, H. Evaluation of
encapsulation techniques for probiotics for yogurt, Int. Dairy J. 13:
3-13 (2003).
5. Cui, JH, Goh, JS, Kim, PH, Choi, SH, Lee, BJ. Survival and
stability of bifidobacteria loaded in alginate poly-l-lysine
microparticles, Int. J. Pharm. 210: 51-59 (2000).
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
Chandramouli, V, Kailasapathy, K, Peiris, P, Jones, M. An improved
method of microencapsulation and its evaluation to protect
Lactobacillus spp. in simulated gastric conditions, J. Microbiol.
Meth. 56: 27-35 (2004).
Krasaekoopt, W, Bhandari, B, Deeth, H. Comparison of texture of
yogurt from conventionally treated milk and UHT milk fortified
with low-heat skim powder, J. Food Sci. 69: 276-280 (2004).
Krasaekoopt, W, Bhandari, B, Deeth, HC. Survival of probiotics
encapsulated in chitosan-coated alginate beads in yoghurt from
UHT- and conventionally treated milk during storage, LWT 39:
177-183 (2006).
Lee, JS, Cha, DS, Park, HJ. Survival of freeze-dried Lactobacillus
bulgaricus KFRI 673 in chitosan-coated calcium alginate
microparticles, J. Agric. Food Chem. 52: 7300-7305 (2004).
Gombotz, WR, Wee, SF. Protein release from alginate matrices,
Adv. Drug Deliv. Rev. 31: 276-283 (1998).
Canh, L, Millette, M, Mateescu, M, Lacroix, M. Modified alginate
and chitosan for lactic acid bacteria immobilization, Biotechnol.
Appl. Bioc. 39: 347-354 (2004).
Gibson, GR, Roberfroid, MB. Dietary modulation of the human
colonic microbial: Introducing the concept of prebiotics, J. Nutr.
125: 1401-1412 (1995).
Bielecka, M, Biedrzycka, E, Majkowska, A. Selection of probiotics
and prebiotics for symbiotic and confirmation of their in vivo
effectiveness, Food Res. Int. 35: 125-131 (2002).
Chen, MJ, Chen, KN, Lin, CW. Optimization of incorporated
prebiotics as coating materials for probiotic microencapsulation, J.
Food Sci. 70: 260-267 (2005).
King, AH. Encapsulation of food ingredients: A review of available
technology, focusing on hydrocolloids. In, Risch, SJ, Reineccius,
GA (eds.), Encapsulation and Controlled Release of Food
Ingredients, American Chemical Society, Washington, DC,
pp213-220 (1995).
Prüße, U, Dalluhn, J, Breford, J, Vorlop, K. Production of spherical
beads by jet cutting, Chem. Eng. Technol. 23: 1105-1110 (2000).
Kailasapathy, K. Microencapsulation of probiotic bacteria:
Technology and potential applications, Curr. Issues Intest.
Microbiol. 3: 39-48 (2002).
Gilliland, SE. Acidophilus milk products: A review of potential
benefits to consumers, J. Dairy Sci. 72: 2483-2494 (1989).
Chen, MJ, Chen, KN, Kuo, YT. Optimal thermotolerance of
Bifidobacterium bifidum in gellan-alginate microparticles,
Biotechnol. Bioeng. 98: 411-419 (2007).
Hansen, LT, Allan-Wojtas, PM, Jin, YL, Paulson, AT. Survival of
Ca-alginate microencapsulated Bifidobacterium spp. in milk and
simulated gastrointestinal conditions, Food Microbiol. 19: 35-45
(2002).
Sheu, TY, Marshall, RT. Microentrapment of lactobacilli in
calcium alginate gels, J. Food Sci. 54: 557-561 (1993).
Kebary, KM, Hussein, SA, Badawi, RM. Improving viability of
bifidobacteria and their effect on frozen ice milk, Egypt. J. Dairy
Sci. 26: 319-337 (1998).
Adhikari, K, Mustapha, A, Grün, IU. Viability of
microencapsulated bifidobacteria in set yogurt during refrigerated
storage, J. Dairy Sci. 83: 1946-1951 (2000).
Khalida, S, Godward, G, Reynolds, N, Arumugaswamy, R, Peiris, P,
Kailasapathy, K. Encapsulation of probiotic bacteria with alginatestarch and evaluation of survival in simulated gastro-intestinal
conditions and in yogurt, Int. Food Microbiol. 62: 47-55 (2000).
Desmond, C, Ross, RP, O’Callaghan, E, Fitzgerald, G, Stanton, C.
Improved survival of Lactobacillus paracasei NFBC 338 in spraydried powders containing gum acacia, J. Appl. Microbiol. 93:
1003-1011 (2002). n
9
From the Vet Group
Interspecies Differences Influencing
Interspecies Extrapolations
Part II of III: Interspecies Differences Influencing the
Absorption of Oral and Parenteral Formulations
Marilyn N. Martinez, Ph.D.
FDA Center for Veterinary Medicine, Rockville, MD, U.S.A.
Oral Drug Products
Interspecies diversity in gastrointestinal (GI) anatomy and physiology reflects the differences in their respective diets (1). The low
fiber, high fat and protein diet of carnivores (e.g., dogs and cats)
lends itself to a relatively simple colon but a well-developed small
intestine (long villi). Pigs, as omnivores, possess a well-developed
small intestine but have a more complex lower intestine to compensate for their diversified diet. The lower intestine of pigs also
allows for dietary fiber fermentation. Herbivores have marked
differences in GI physiology, as described below.
Understanding the physico-chemical properties of a compound
(e.g., pKa, hydrophilicity) and the effect of formulation on
product dissolution rate is critical when developing formulations
that are intended to be used in more than one animal species.
Marked interspecies differences in mean bile flow and
composition can also affect drug solubilization and, therefore,
drug absorption (2). Although rats and horses have no gall
bladders, both species synthesize bile salts, and bile entry to the
intestine occurs in a more or less continuous manner.
The GI physiology of four veterinary species is described below.
Horses. Due both to the highly variable pH of equine gastric contents (pH = 1.3–6.8, mean = 5.5) and the highly fibrous equine
diet, drug absorption may be poor in much of the small intestine.
This is particularly true for weak bases (where the higher pH will
interfere with drug dissolution) and for drugs whose dissolution
will be impaired by the decrease in diffusivity caused by the viscosity of ingested fibrous materials. Consequently, a large fraction
of drug absorption in horses often occurs in the large intestine.
Two other unique features of the equine GI tract are the lack of a
gall bladder and a relative inability to vomit (3).
markedly improved over that of the horse. This difference enables
ruminants to reduce grazing time from the 18 hr per day
associated with horses to only 6–8 hr per day (3,4). The rumen is
a fermentation vat that can hold 100–225 L in cattle and 10–24
L in sheep and goats. It also contains approximately 150 billion
microorganisms per teaspoon. The condition of the rumen
reflects the environment necessary to maintain its microflora,
including a temperature that ranges from 100 to 108°F and
between a pH of 5.8 and 6.4.
Few drugs, with the exception of sulfa drugs, can resist chemical
degradation in the harsh environment of the abomasum of a
ruminating cow. In contrast, drugs such as trimethoprim are
degraded within the rumen.
Carnivores. Carnivores generally possess a relatively simple
colon and a well-developed small intestine (long villi). Canine
GI transit time is markedly faster than that of humans. Dogs
tend to have a lower (fasting) basal acid secretion than do
humans (5), leading to a higher pH, ranging between 1 and
about 6. Conversely, following a meal gastric acid secretion rates
in dogs exceed those of humans and slowly return to baseline,
leading to a lower gastric pH compared with the postprandial
human stomach. The higher pH found in the small intestine of
dogs (versus that in humans) may result in better absorption of
drugs that are weak bases.
Equines are hindgut fermentors, with a small intestine whose
fluid capacity is substantially less than that of the large intestine.
Due to the poor absorption of the other nutrients released in the
hindgut, equids need to consume food for about 18 hr per day to
meet their nutrient requirements.
Ruminants. Because fermentation of fiber takes place proximal
to the small intestine, the efficiency of nutrient absorption is
10
Common veterinary animals that highlight the diversity in gastrointestinal
anatomy—Jock the border collie (left) and a Hereford cow with her calf (right).
Photos by Arlene McDowell.
For palatable formulations, the selection of a flavorant depends
on the flavor and odor preferences of the intended targeted
animal species. Cats are attracted to meat, fish, liver, and yeast
flavors. Dogs are attracted to meat, liver, chicken, yeast, and
sugars (6). Cats also have neither an attraction nor an aversion to
sweet carbohydrates (7).
Parenteral Drug Products
The relative bioavailability of IM or SC dosage forms may not
be comparable across animal species. Rather, numerous biological
factors can influence absorption (e.g., absorptive area, injection
volume, blood and lymph flow, exercise, local pH, ionic
composition of extracellular fluids, drug or excipient binding
to tissues, drug diffusivity through the formulation and injection
site, and local drug metabolism [8,9]). Solubilized drug can
also re-precipitate at the site of injection due to preferential
absorption of the vehicle or the effect of local pH on drug
solubility.
Interspecies differences in injection site also need to be
considered, particularly with food producing animals, where sites
are often selected on the basis of minimizing the loss of quality
or residues associated with edible tissues.
Sustained Release (SR) Formulations
SR tablet formulations provide an important tool for enhancing
patient compliance. Likewise, within veterinary medicine there is
an ever-growing demand for long-acting products. However, the
rapid GI transit time of dogs, along with the very strong
crushing force of the canine stomach makes it difficult to
formulate SR oral products (10). For this reason, the
development of alternative gastric-retention systems may be
particularly important in companion animal medicine, including
gastro-retention devices, systems that lodge themselves in the
stomach by altering their geometric configuration upon exposure
to gastric fluids, and mucoadhesive systems.
With regard to parenteral products, an increasing number of
veterinary dosage forms are being developed for prolonged
(months) release. In these instances, parenteral formulations (e.g.,
microspheres, implants, in situ forming gels, lipophilic solutions,
and suspensions) are of great interest. An upcoming review of
the 2007 CRS Educational Workshop (Martinez, Burgess,
Huynh, and Rathbone, to be submitted to the Journal of
Controlled Release) will provide a synopsis of the interspecies
considerations associated with the development of these
formulations.
The final installment, “Interspecies Differences in Metabolism
and Toxicology,” will appear in the next CRS Newsletter.
References
1. Martinez, M, Amidon, G, Clarke, L, Warren Jones, W, Mitra, A,
Riviere, J. Applying the biopharmaceutics classification system to
veterinary pharmaceutical products: Part II: Physiological
considerations, Adv. Drug Deliv. Rev. 54: 825-850 (2002).
2. Riviere, JE. Comparative Pharmacokinetics: Principles, Techniques
and Applications, Iowa State University Press, Ames, IA, p101
(1999).
3. Baggot, JD, Brown, SA. Basis for selection of the dosage form. In:
Hardee, GE, Baggot, JD (eds.), Development and Formulation of
Veterinary Dosage Forms, 2nd Edition, Marcel Dekker, New York,
pp7-143 (1998).
4. Anonymous. From Feed to Milk: Understanding Rumen Function,
Pennsylvania State College of Agriculture Sciences, College Park,
PA, 1996.
5. de Zwart, LL, Rompelberg, CJM, Sips, AJAM, Welink, J, van
Engelen, JGM. RIVM Report 62386010: Anatomical and
physiological differences between various species used in studies on
the pharmacokinetics and toxicology of xenobiotics, A review of
literature, Published online at www.rivm.nl/bibliotheek/
rapporten/623860010.html (1999).
6. Ehrlein, HJ, Pröve, J. Effect of viscosity of test meals on gastric
emptying in dogs, Q. J. Exp. Physiol. 67: 419-425 (1982).
7. Li, X, Wang, H, Bayley, DL, Cao, J, Reed, DR, Bachmanov, AA,
Huang, L, Legrand-Defretin, V, Beauchamp, GK, Brand, JG. Cats
lack a sweet taste receptor, J. Nutr. 136: 1932S-1934S (2006).
8. MacDiarmid (1983).
9. Pope (1984).
10. Martinez, MN, Papich, Submitted to J. Pharm. Sci. n
11
From the Education Committee
Back to Basics: 1. Tissue and Cell Culture
Sarah E. McNeil
Life and Health Sciences, Aston University, Birmingham, U.K.
This is the first in a series of articles introducing the basics of different
research methods and techniques that may be required for the successful
development and evaluation of controlled release technologies.
What Is Cell Culture and Why Do We Use It?
Cell culture is a technique whereby cells/tissues derived from
either animal, human, or plant origin are isolated and grown
within a controlled artificial environment. The simulated
environment, if possible, should mimic the normal conditions
found within the living organism from which the cells are
derived. The cells should remain metabolically active, replicate,
and grow in this environment. The use of cell culture studies, by
application of in vitro cell cultures may provide solutions to in
vivo challenges. Numerous studies covering an immense number
of different topics and that have applied the use of cell culture
have been conducted. Although the ultimate goal of these studies
may vary, the basic cell culture technique is similar.
History and Recent Advances in Use of Cell Culture
The reported use of cell culture dates back to the early 1900s,
when Harrison was able to successfully cultivate nerve cells in
vitro. Following this revolutionary demonstration of cell isolation
and growth outside the human body, Carrel and co-workers in
1911 were able to successfully culture embryonic and adult tissue
cells, continually making great strides and contributions to cell
culture, the development of various media and medium
supplements, and the improvement of cell cultivation by use of
cell culture flasks (1). Strangeways in 1919 demonstrated success
using this technique. However, it was not until the 1940s and
1950s that sterilisation was used to avoid the risk of
contamination of cell lines and tissue cultures. This was achieved
by use of laminar flow hoods and antibiotics in the culture media.
A vast number of recent studies have used cell culture,
illustrating the adaptive use of this technique within various
areas of scientific interest. These have included studying the
principles of cell biology, the effects of various classes of
pharmacological agents on cells, vaccine production,
immunology, aging, and nutritional studies, amongst others. For
example, mononuclear cells have been isolated from blood
samples of cancer patients and cultured in vitro. By activating
these mononuclear cells in culture it was found that there was a
reduction in the IL-2 response in breast cancer patients, with a
depression of IL-2 levels correlating with the stage of the disease.
Thus, measuring IL-2 production in breast cancer patients may
contribute to their prognosis (2). Cell culture has also been used
12
as an in vitro model to assess and measure the cellular and
histological effects of smoking (3), and there are an extensive
number of studies investigating the ability of various lipid-based
vaccines to effectively transfect cells in vitro (4–7).
Essentials of Cell Culture
One of the main and most crucial challenges when working with
cells in culture is keeping the cells healthy and alive. Prior to
commencing any cell culture, the design and set-up of a cell
culture laboratory must be addressed. This is vital in order to
maintain a safe and efficient working environment. In order to
avoid cross-contamination, individual work should be carried out
separately either by area or time. In addition to the risks
associated with cell contamination, the risks presented to the
worker are also of utmost importance. As outlined in the
“Biological Agents: Managing the Risks in Laboratories and
Healthcare Premises” guidelines published by the Advisory
Committee on Dangerous Pathogens (8), the risks associated
with working with cell lines need to be considered prior to cell
work being started. In particular the origin, source, and type of
cell line must be taken into account.
Cell Culture: The Basics. There are a set of general procedures and
rules that are used in cell culture, irrespective of the experimental
purpose of the study undertaken. Primarily, it is essential that the
laminar flow hood in which cell culture work is to take place be
sterilised. Sterility is achieved by applying ultraviolet light (UV)
to the working area for at least 10 min prior to use and
subsequently by spraying the working area liberally with 70%,
vol/vol, alcohol. Furthermore, it is critical that all surfaces and
items within or introduced into the hood be kept completely
sterile at all times.
I. Resuscitation of a frozen cell line
This initial step involves re-establishing the cell line or bringing
the cells “back to life”! Cells are usually frozen in liquid nitrogen
in order to maintain cell integrity over an extended period of
time, and therefore, prior to any experimental procedures, the
cells of interest must be thawed in a relatively quick but
controlled manner to maintain their integrity. This procedure is
usually carried out in four simple steps:
Preparation: Under sterile conditions, in the laminar flow
hood, cell culture flasks should be prepared by
adding the desired volume of the appropriate
pre-warmed culture medium relevant for the
cell line to be established. The outside of the
flask should be labelled, detailing the cell line,
passage number, and worker’s name and date.
Thawing:
The cells should be removed from the liquid
nitrogen storage tank, whilst wearing
protective clothing to avoid contact with
liquid nitrogen, and placed within a water
bath set at the appropriate temperature (i.e.,
25°C for insect cells and 37°C for mammalian
cells), until the cells are fully thawed.
Sterilisation: The outside of the container in which the cells
are kept needs to be sterilised, which should
be done by wiping the outside with 70%
alcohol. The container can then be placed in
the sterile hood.
Growing:
The cell suspension should be carefully
transferred into the cell culture flask,
containing pre-warmed medium, and placed
in an incubator set at the appropriate
temperature, with supply of the correct
amount of CO2.
II. Subculture of Adherent Cells
Cells will grow and adhere to the bottom of the tissue culture
flask until they reach 90–100% confluence. Confluence is the
point at which the cells cover the bottom of the flask completely
(Figure 1). At this crucial stage, the cells must be subcultured/
passaged to reduce the number of cells present. At this point replenishment of the “old” medium with “new,” fresh medium and
nutrients to enable the cells to continue growing over a longer
period of time is essential. Cells will die if left to continue growing in overpopulated environments, due to lack of space and nutrients. (Note: the growth medium should be pre-warmed to the
desired temperature for the cells prior to addition to the flasks).
Removal:
The flask containing the relevant cells must be
removed from the incubator and sterilised by
careful spraying of the outside of the flask with
70% alcohol. The “old” medium is then
removed and discarded as biological waste.
Detachment: Trypsin/EDTA solution should be added to
the cells and then incubated for 5 min. To
ensure that the cells have been completely
detached from the flask, tap the side flask
gently.
Figure 1. Cell culture flasks containing growth medium with nutrients
essential for cell growth, with cells adhering to the bottom of each flask.
Dilution:
Washing:
Growing:
The growth medium should be added to the
flask to dilute the trypsin/EDTA solution. It is
at this stage that the number of cultivated cells
can be readily quantified as described below.
To remove trypsin from the cell solution, an
optional washing step may be introduced. At
this stage the cell suspension should be
transferred to a sterile centrifuge tube and
centrifuged to obtain a cell pellet. The
supernatant (i.e., medium) should be removed
carefully without disturbing the cell pellet. The
cell pellet can be removed and then must be
fully resuspended with fresh growth medium
to maintain cell viability.
A portion of the cell suspension should be
carefully transferred into a cell culture flask,
containing pre-warmed medium and placed in
an incubator set at the appropriate
temperature, with a supply of the correct
amount of CO2 to permit continued growth.
III. Cell Quantification
Removal:
200 µL of the cell suspension to be quantified
must be removed from the solution (II) under
sterile conditions.
Staining:
An equal volume of trypan blue solution is
then added to this cell suspension and mixed
thoroughly.
Counting: A 10-µL aliquot of this solution is added to
each side of an haemocytometer (i.e., a thick
glass microscope slide, with laser engraved
grids) to determine cell counts, using the light
microscope. Live cells are brighter and more
visible than dead cells and, therefore, can be
quantified.
IV. Cryopreservation of Cell Lines
Counting: Cells should be quantified (III) to determine
the correct dilution and concentration of cells
to freeze down (e.g., 4 × 106 cells/mL) for
future use.
Washing:
The cell suspension should be transferred to a
sterile centrifuge tube and centrifuged to
obtain a cell pellet. Under laminar flow the
supernatant (i.e., medium) should be removed
carefully without disturbing the cell pellet. The
cell pellet should be resuspended fully with
cryopreservation medium suitable for the
specific cell line (e.g., 90% foetal bovine serum
and 10% DMSO).
Splitting:
Following suspension, the cell pellet should be
separated into 1-mL aliquots and transferred
into sterilised ampoules designed for
cryopreservation. The ampoules should be fully
labelled, stating cell line, passage number, date,
and cell concentration prior to sealing.
Back to Basics continued on page 14
13
Back to Basics continued from page 13
Freezing:
The ampoules should be placed at –70°C
overnight and subsequently transferred to a
liquid nitrogen container for storage until the
cells are required for use.
Following these steps should take you back to the basics of cell
cultivation, harvesting, and evaluation. This article is intended to
provide some of the basic and essential tools and instructions for
effective use of cells and provide all potential cell culture users
with a valuable starting point, so that when using microscopy
your results will be as good as those depicted in Figure 2.
References
1.
2.
3.
4.
5.
6.
7.
Figure 2. Adherent bone-derived cells growing in in vitro conditions. (Photo
courtesy of Dr. Richard M. Shelton and Dr. Jonathan Harris, Birmingham
University, UK, and Prof. Yvonne Perrie and Dr. Alan Smith, Aston
University, UK).
8.
Carrel, A, Burrows, MT. Cultivation of tissues in vitro and its
technique, J. Exp. Med. 13: 387-396 (1911).
Kell, M, Conneely, J, O’Toole, P, Winter, D, Beddy, D, Watson, W,
Fitzpatrick, J, Kerin, M. T-cells and molecular prognosis profiling
in breast cancer, J. Am. Coll. Surgeons 199(3, Suppl. 1): 78-78
(2004).
Bernhard, D, Huck, CW, Jakschitz, T, Pfister, G, Henderson, B,
Bonn, GK, Wick, G. Development and evaluation of an in vitro
model for the analysis of cigarette smoke effects on cultured cells
and tissues, J. Pharmacolog. Toxicolog. Meth. 50(1): 45-51 (2004).
Chen, JL, Wang, H, Gao, JQ, Chen, HL, Liang, WQ. Liposomes
modified with polycation used for gene delivery: Preparation,
characterization and transfection in vitro, Int. J. Pharmaceut. 343:
255-261 (2007).
Hirsch-Lerner, D, Zhang, M, Eliyahu, H, Ferrari, ME, Wheeler,
CJ, Barenholz, Y. Effect of “helper lipid” on lipoplex electrostatics,
Biochim. Biophys. Acta Biomembranes 1714(2): 71-84 (2005).
Maitani, Y, Aso, Y, Yamada, A, Yoshioka, S. Effect of sugars on
storage stability of lyophilized liposome/DNA complexes with
high transfection efficiency, Int. J. Pharmaceut. 356: 69-75 (2008).
Sternberg, B, Hong, K, Zheng, W, Papahadjopoulos, D.
Ultrastructural characterization of cationic liposome-DNA
complexes showing enhanced stability in serum and high
transfection activity in vivo, Biochim. Biophys. Acta Biomembranes
1375(1-2): 23-35 (1998).
Health and Safety Executive. Biological agents: Managing the risks
in laboratories and healthcare premises. Advisory Committee on
Dangerous Pathogens. Published online at www.hse.gov.uk/
biosafety/biologagents.pdf (2005). n
The CRS Foundation
Established in 2007 with a clear vision …
to provide a durable source of financial support for the advancement of
educational and organizational activities that enrich and extend the research
and development of CRS-associated technology platforms involved in the
delivery of bioactives in pharmaceutical, non-pharmaceutical active ingredients,
and in animal-health related fields
… the CRS Foundation needs your
help to positively impact the future.
To learn more about the CRS Foundation
Visit with a member of the CRS Board of Directors or contact
Deborah Woodard at [email protected] or +1.651.994.3817.
FOUNDATION
14
Chapter News
8th International Symposium on
NDDS Organised by CRS Indian Chapter
The CRS Indian Chapter (CRS-IC) held its 8th International
Symposium, “Advances in Technology & Business Potential of
New Drug Delivery Systems,” February 26–27, 2008, at the B.V.
Patel PERD Centre, Ahmedabad, India.
The symposium was opened by Shri Dilipbhai Shanghvi, chair
and managing director of Sun Pharmaceutical Industries Ltd.,
India, who also kindly released the book of abstracts. The
inaugural function was presided over by Shri Ajit Singh,
president of CRS-IC. He welcomed the guests, speakers,
members of the International Advisory Board, and delegates.
Shri Anantbhai Thakore, co-chair of the symposium and chair of
the Board of Trustees of the B.V. Patel PERD Centre, gave an
Left to right: Prof. H. L. Bhalla, emeritus president CRS-IC and chair of the
Scientific Committee; Dilip Shanghavi, chief guest of the function and chair
and managing director of Sun Pharma Industries Ltd., India; Prof. T.
Nagai, guest of honour and chair of the Nagai Foundation, Tokyo, Japan;
Prof. Leslie Benet, keynote speaker; Anant Thakore, co-chair of the
Organizing Committee and chair of Anant & Co., India; and Dr. K. K.
Singh, secretary of CRS-IC.
introduction on the centre and welcomed everyone on its behalf.
Prof. T. Nagai, the guest of honour, released the first issue of the
Newsletter of the CRS Indian Chapter. Prof. H. L. Bhalla
introduced the participating dignitaries, and Prof. K. K. Singh,
secretary of CRS-IC, proposed a vote of thanks. The scientific
proceedings started with a keynote address, “Recent Advances in
Biopharmaceutics: BCS and BDDCS,” given by Prof. Les Benet.
This was followed by as many as 15 invited talks by distinguished
scientists from India and abroad. In addition, there was a special
session on excipients, in which two representatives of excipient
manufacturers discussed their products.
The symposium has increased steadily in strength, and this year
there was significantly more participation from industry and
academia. The symposium attracted more than 350 delegates and
about 150 poster presentations. The concluding function was
conducted by Prof. H. L. Bhalla. He announced the names of the
winners of the 1st and 2nd place prizes for the Best Poster and
gave the certificates and prizes to the candidates in his capacity
as chair of the Scientific Committee. The 1st prize for Best
Poster was awarded to Ritnesh Jain and Dr. V. B. Patravale. The
2nd prize was shared by Poonam Saraf and Prof. P. V. Devarajan
and Pooja Sachan and Prof. K. K. Singh. Thereafter, Prof. Bhalla
invited faculty members and interested delegates to express their
opinions about the proceedings and make suggestions for
improving the quality of future meetings. Many guests speakers
from abroad praised the quality of the oral and poster
presentations, as well as the hospitality and other arrangements.
Prof. Bhalla concluded the session by expressing his gratitude to
all who made the symposium a grand success and declared the
closing of the proceedings. n
Attendees enjoy the technical program during the 8th International
Symposium, “Advances in Technology & Business Potential of New Drug
Delivery Systems.”
2007 Meeting of the CRS Italian Chapter
Paolo Caliceti
University of Padua, Padua, Italy
The 2007 Meeting of the CRS Italian Chapter took place in
Rimini, Italy, on Thursday, June 14, as a satellite symposium of
the 47th AFI Congress, the annual congress of the Italian
Association of Pharmaceutical Industry. The joint AFI/CRS
Italian Chapter symposium offered an excellent opportunity for
Italian scientists and product developers working in the field of
drug delivery to enhance cooperation between academia and
industry.
According to the recently introduced trend, the CRS Italian
Chapter contributed to the AFI congress by organizing a 1-day
scientific session on drug delivery systems titled “Research and
Development: New Technologies for Controlled Drug Delivery.”
The symposium was organized as a podium presentation/soap
box, where both public and private institutions shared their
knowledge, expertise, and scientific projects at the forefront of
drug delivery and technological advances.
Chapter News continued on page 16
15
Chapter News continued from page 15
Due to the large number of attendees, the symposium was
divided in two parallel sessions. Chairs Prof. C. Caramella (Pavia
University) and Dr. A. Tajana (AFI) welcomed the attendees and
briefly introduced the aim of the meeting. A total of 61 speakers
was involved—40 were representatives of 19 universities, and the
remaining 21 were from industry. Each presentation had a time
limit of 10 minutes and described research projects, know-how,
and perspectives on exploitation in pharmaceutics.
Representatives from private companies showcased the strongly
applicative target of their activities. Alpex Pharma, Flarer SA,
IMA Dolida Dose Division, Farmatron, Bouty, Rofarma,
Qualicaps, Cardinal Health, and APR presented a variety of
projects involving oral delivery, ranging from multi-matrix
systems for controlled drug release to film technology for oral
dispersible tablets, lipid particles to chewable medications, and
buccal to colon delivery.
The relevance of new industrial technologies for the development
of oral therapeutic systems was highlighted by Pfizer and
E-Pharma, which reported on innovative methods of industrial
material processing, namely granulation and capsule filling.
Speakers from Valois, Chiesi, and Eratch emphasized the
industry’s interest in the development of inhalation drug delivery
systems, while those from Monteresearch and Bouty presented
projects on vaginal and transdermal delivery. Finally, Micro-
Sphere, Sitec, Nanovector, Eurand, and Vitroscreen reported
progress on micro- and nanotechnology know-how and
applicability in the drug delivery field.
The university groups presented a variety of projects and
evidenced their intense research activities in a broad and modern
scientific scenario. The speakers presented projects highlighting
the applicability of their research efforts, ranging from microand nano-particles to mucoadhesive systems, ophthalmic to oral
delivery, and bioconjugation to mathematical design.
After each session, in order to facilitate the exchange of
information between speakers and audience, the various topics
presented were discussed within smaller groups in a more
informal atmosphere. Most participants enjoyed the interactive
setup of the event and described the meeting as a professionally
and socially rewarding experience.
During the evening assembly of the CRS Italian Chapter, the
President Dr. Pedrani briefed the members on the formal
procedure adopted in order to obtain the official status of the
Association and announced the election of the Directive
Council. Dr. Pedrani further reported on activities co-sponsored
by the CRS Italian Chapter in 2007 (workshop on “Biotech
Drug Development,” March 7–8, Pavia; workshop on “Advances
in Drug Delivery for Inhalation,” April 23, Milan) and informed
the audience about the CRS activities planned for the upcoming
months. n
New Zealand Chapter of CRS Holds 10th
Formulation and Drug Delivery Conference in Dunedin
Dr. Karen Krauel-Goellner
Institute of Food Nutrition and Human Health, Massey University, Wellington, New Zealand
Approximately 100 delegates gathered in Dunedin, New
Zealand, for the 10th Formulation and Drug Delivery
Conference in February of this year. With an additional day and
more international speakers, the conference promised to be
better than ever. Prof. Ian Tucker, dean of New Zealand’s
National School of Pharmacy and convenor of the Formulation
and Drug Delivery (FDD) Research Theme at the University of
Otago gave the opening address. He pointed out the
interdisciplinary theme of this conference, with delegates having
very diverse research interests, from pharmaceutical to
immunological and agricultural. It is this interdisciplinary nature
that has proven to be so successful over the years and given the
opportunity for so many collaborative projects.
The first day kicked off with sessions on colloidal drug and
vaccine delivery and solid-state issues in drug delivery. Prof.
Jayne Lawrence from King’s College in London was the New
Zealand Chapter of CRS (NZCRS) keynote speaker, and she
gave an excellent overview of the use of neutron scattering in the
16
characterisation of
colloidal systems.
Various colloidal
systems for vaccine and
drug delivery are also
investigated in the New
Zealand, but due to lack
of instrumentation,
neutron scattering so far
has not been a
characterisation option. NZCRS Keynote Speaker Prof. Jayne
Hopefully this will
Lawrence and Prof. Thomas Rades (NZCRS
change, and a
president).
collaboration can be
established between Jayne Lawrence’s group and the groups in
New Zealand. The afternoon session started with a presentation
by Dr. Robert Lancaster (University College, London, and
formerly Pfizer), who gave the captive audience insight into the
world of disappearing polymorphs and crystal structure
Keynote Speaker Prof. David Jones and Dr.
Natalie Medlicott (School of Pharmacy,
Dunedin).
prediction based on
his 30 years of
experience in the
solid-state area. Prof.
Elisabeth Topp from
the University of
Kansas gave an
interesting spin in
the solid-state session
with her presentation
on protein stability in
amorphous solids.
The theme of the
second day was biological issues in drug and vaccine delivery.
Having been a lecturer at the School of Pharmacy in Dunedin a
few years back, the keynote speaker for this session was a familiar
face to many attendees. Prof. David Jones (Queens University,
Belfast) introduced us to the world of controlled release issues in
medical devices and gave an excellent overview of how his
research is trying to overcome release issues caused by
encrustation, microbial biofilms, etc. by using drug-polymer
conjugates, stimulus sensitive polymers, and facilitated drug
diffusion from bioactive materials. David’s talk was followed by a
presentation by Prof. Claus-Michael Lehr (Univeristaet des
Saarlandes, Saarbruecken) who gave an account of investigating
the transport of nanoparticles across biological barriers, especially
human skin and alveolar epithelial cells. The afternoon session
was concerned with vaccine delivery before everyone got ready for
the conference dinner. For the first time this year the conference
organisers introduced a Limerick competition under the theme of
formulation and drug delivery, and a group of postgraduate
students won.
Further presentations were
concerned with drug
delivery formulation for
livestock animals and
control of pest wildlife.
Before the closing remarks
of the conference were
given, the student prizes
had to be handed out. As in
every year, the competition
was strong, and Dr. Robert
Lancaster took the
opportunity to congratulate
all the students on their
excellent efforts and made
the comment that he envies
them for their PowerPoint
skills. Through the
competition, the NZCRS
recognises the student’s
research efforts and
supports the attendance of
students at the annual CRS
meeting. The winners of
this year’s competition were
Julia Myschik (School of
Prize winners of the 2008 NZCRS
Pharmacy, University of
student prize. Top: Julia Myschik; middle:
Otago), Bradley McLellan Bradley McLellan; and bottom:
(University of Waikato),
Shakila Rizwan.
and Shakila Rizwan
(School of Pharmacy,
University of Otago). Since Julia had won the first prize already
the year before and did not intend to go to New York, the prize
money was deferred to the 2nd and 3rd place winners. So, see
you in New York Bradley and Shakila.
Because this was the 10th anniversary of the conference, things
need to be bigger and better, and an extra day was dedicated to
the veterinary session, this being of particular
interest to New Zealand because of its big
livestock industry and unique wildlife, which
needs protection from pests. Dr. Marilyn
Martinez from the U.S. FDA for Veterinary
Medicine presented her views on factors that
influence the gastric transit, solubility and
permeability of oral dosage forms in dogs and
pointed out that these differences have to be
taken into account when developing medicines
for dogs, while also highlighting the
comparability issues between humans and dogs Attendees at the 10th Formulation and Drug Delivery conference in Dunedin.
in clinical studies. Unfortunately Dr. Martinez
could not give her presentation in person, but
had to send over her slide show and present her findings over the
The 10th anniversary of this meeting brought together a great
phone. The next speaker, Dr. Hans-Juergen Haman from Bayer
variety of outstanding researchers; every day was filled with
Health Care (Germany), did a great job in drawing our attention
excellent presentations, and the extra day for the vet session was
to the challenging task of developing controlled release topical
well received. The great momentum gained from this meeting
formulations for animals. The limited variety of drugs, the special
will certainly be carried over to next year ,when the 11th meeting
topical conditions of animals, and the necessary ease of
will be held in Dunedin. See you then. n
application prove a great challenge for the formulation team.
Chapter News continued on page 18
17
Chapter News continued from page 17
CRS Nordic Chapter Annual Meeting to Be
Held in Tromsø, Norway
The 2008 Annual Meeting of the CRS Nordic Chapter will be
held June 25–27 in conjunction with the 2nd Midnight Sun
Meeting on Drug Transport & Delivery at the University of
Tromsø, Norway. This 3-day meeting is meant to be a rather
informal gathering of scientists who are interested in drug
transport and delivery, from basic research to applied research
and pharmaceutical development points of view. As in 2004,
when the meeting was first held, the organisers expect about 100
participants from all over Europe (mainly Scandinavia) and
from both academia and industry. The meeting will be hosted by
the Drug Transport & Delivery-Group, Department of
Pharmacy, University of Tromsø, with support from the
Controlled Release Society Nordic Chapter. The meeting is
strictly non-profit in nature.
The focus areas will be
• Drug solubility, analysis, prediction, and ways to overcome
poor solubility
• Drug permeability, drug transporters, and permeability
screening
• Drug delivery, nano drug carriers; and oral dosage forms
Each of the scientific sessions will be opened by a comprehensive
talk given by a leader in the field, followed by a number of short
oral communications selected from the submitted abstracts and
complemented by a poster session and networking opportunities.
Speakers list:
Dr. Christel Bergström, Uppsala University, Department of
Pharmacy, Screening Informatic Center
Dr. Matthias Brandsch, Martin-Luther-Universität HalleWittenberg, Biozentrum, Membrane Transport Group
Prof. Dr. Heike Bunjes, TU Carolo Wilhelmina Braunschweig,
Inst. f. Pharmazeutische Technologie
Prof. em. Dr. Henning Gjelstrup Kristensen, University of
Copenhagen, Faculty of Pharmaceutical Sciences, Dept.
Pharmaceutics
Dr. Anna Lena Ungell, AstraZeneca R&D Mölndal, Discovery
Drug Metabolism and Pharmacokinetics & Bioanal.
Chemistry
Tromsø, the “capital” of northern Norway is easily reached by a
2-hour flight from Oslo. During the short yet intense summer,
Tromsø is “the” starting point for excursions to the arctic.
For updated information please check the meeting homepage at
http://uit.no/farmasi/4090/. n
UKICRS Conference Review: 14th Annual Symposium 2008
Predicting Drug Delivery—Opportunities and Challenges
The 14th UKICRS Annual Symposium on “Predicting Drug
Delivery—Opportunities and Challenges” was held at Merck
Sharp and Dohme, United Kingdom, on Wednesday, January 23,
2008. The Symposium Organising Committee members were
Dr. Leab Sek (Merck Sharp & Dohme), Dr. Abina Crean
(University College Cork), Dr. Sarah Dexter (3M Health Care),
and Dr. Majella Lane (School of Pharmacy University of
London). The 14th UKICRS Symposium was highly successful,
with approximately 85 registered delegates from the
pharmaceutical industry and academia.
Dr. Shaun Fitzpatrick (Merck Sharp & Dohme) opened the
morning session with a presentation titled, “Predicting Drug
Delivery—An Industrial Perspective.” The presentation
highlighted the advantages and challenges associated with the
development of oral controlled release dosage forms, including
matrix and multiparticulate drug delivery systems.
Multiparticulate extended-release delivery systems require
relatively more complex developments and higher cost
manufacturing techniques. In comparison, matrix extendedrelease delivery systems are cost-effective and simple to develop
18
using readily available manufacturing technologies. The main
limitation for this type of dosage form is the propensity to
produce different blood exposure levels when taken with or
without food. Whilst there are different in vitro techniques, such
as USP Apparatus I and II and more recently Apparatus III and
IV, available to predict formulation performance in humans,
further developments in this area are required.
Dr. Cormac Taylor’s (University College Dublin) presentation
was titled, “The Hydroxylase Inhibitor DMOG Is Protective in a
Murine Model of Colitis.” Prolyl and asparaginyl hydroxylases
are key oxygen-sensing enzymes that confer hypoxic sensitivity
to transcriptional regulatory pathways, including the His studies
investigating the effects of hydroxylase inhibition with
dimethyloxalylglycine (DMOG) on Caco-2 intestinal epithelial
cells in vitro (Caco-2) and in a dextran sodium sulphate
(DSS)-induced model of murine colitis that demonstrates that
hydroxylase inhibitors such as DMOG represent a new strategy
for the treatment of inflammatory bowel disease.
Prof. Mark Cronin (Liverpool John Moores University) discussed
“In Silico Prediction of Properties Relating to Dermal Drug
Delivery.” For dermal delivery, there has been a considerable
history of using QSARs to predict various aspects of skin
permeability, using a variety of techniques to develop models.
Typically most success has been achieved with the modelling of
steady-state phenomena such as the permeability coefficient (Kp).
This is because this type of data is most amenable to modelling.
Some of the databases (e.g., the now classic “Flynn” data set and
its updated versions) have been modelled by a variety of
approaches, ranging from simple regression analyses based on
hydrophobicity and molecular size to more complex models with
non-linear methods. In other areas, in silico predictions can be
made for other physico-chemical properties, such as melting
point, aqueous solubility, vapour pressure, and Henry’s law
constant, with varying degrees of accuracy.
The presentation by Dr. Ben Forbes (King’s College London)
highlighted strategies for “Predicting Drug Delivery to the
Lung.” The factors determining the fate of an inhaled medicine
include aerosolisation and particle deposition, dissolution, drug
metabolism, transport by the mucociliary escalator, macrophage
uptake, and transepithelial absorption. A number of in vitro
systems are available to study the interaction of compounds and
formulations with components of the respiratory tract, such as
cell culture models of the respiratory epithelium and the isolated
perfused lung.
The afternoon session was opened by an international guest
speaker, Prof. Rod Walker (Rhodes University, South Africa),
who provided an overview on “Paediatric Drug Product Development: Opportunities and Challenges.” The presentation looked at
paediatric drug product development and the various regulatory
and technical hurdles that face scientists designing delivery systems for such patients. The opportunities that exist for novel delivery system design for this patient population and some examples were presented. Challenges for paediatric drug delivery in
the developing world and the opportunities for innovation that
arise from such challenges were also addressed.
Highlights of current postgraduate drug delivery research
included Waleed Faisal (University College Cork) on
“Investigations of Lycopene Absorption Mechanisms from the
Gastro-intestinal Tract of the Rat.” Daniel Wood (University of
Hertfordshire) presented his research work on
“Thermoenhancement of Percutaneous Drug Absorption.” Sam
Maher (University College Dublin) also presented his studies on
“Increased Intestinal Permeability Induced by Melittin.”
Prof. Marc Brown (University
of Hertfordshire and
MedPharm Ltd.) provided a
comprehensive overview on “In
Vitro Models for Optimising
Ungual Drug Delivery.” The
presentation described the new
generation of in vitro models
and methodologies that are
being used to 1) gain a more
fundamental understanding of
the barrier properties of the
nail, 2) develop and optimise
Graduate presentation winner Sam
ungual formulations to aid the
Maher (left) and UKICRS Chair
development of the next
Yvonne Perrie (right).
generation of topical ungual
formulations, and 3) decrease the risk of failure when such
medicinal products enter clinical evaluation.
Closing the symposium, Dr. Michael Donaldson (Stiefel
Laboratories) spoke on “In-Vivo Models for Predicting
Transdermal Delivery.” The presentation highlighted in vitro
techniques and in vivo models for predicting transdermal
absorption and toxicity. In terms of measuring diffusion, there is
a range of systems, several of which came online just recently;
however, the simplest model is the nail swelling model, which
assumes an increase in the weight of the nail is directly
proportional to drug uptake. However, both Michael and Mark
noted that new ethical procedures made it much more difficult to
actually obtain nail samples, so even this method had limitations.
The UKICRS annual student award for Best Postgraduate
Presentation was won by Dr. Sam Maher (University College
Dublin) for his research on “Increased Intestinal Permeability
Induced by Milittin.” Nick Gower (University of Bristol), along
with Dr. Paolo Avalle and Anna Midwinter from Merck Sharp
& Dohme, won the Best Poster Award for their work on “The
Use of NIR Spectroscopy to Study the Hydration of a
Controlled Release Tablet.”
The UKICRS Committee would like to thank all the speakers
for their contributions in delivering an excellent program. The
UKICRS Committee gratefully acknowledges Merck Sharp &
Dohme as the main sponsor of the symposium and Aqualon and
CRS for financial support. The committee would like to also
thank the exhibitors at the symposium, including Journal of
Pharmacy and Pharmacology, Eminate, Wyatt Technology,
Horiba, and Oxford Instruments. n
Left to right: Symposium chairs and presenters: Abina Crean, Mark Cronin,
Daniel Wood, Leab Sek, Yvonne Perrie, Sarah Dexter, Michael Donaldson,
Shaun Fitzpatrick, Rod Walker, Marc Brown, Ben Forbes, Sam Maher, and
Waleed Faisal.
19
35th CRS Annual Meeting & Exposition
Why You Absolutely Have To Be There
Ijeoma F. Uchegbu
CRS Scientific Secretary, University of London, U.K.
It is not often that things work out so well
as our planning for the 35th CRS Annual
Meeting & Exposition, especially in the
world of science, where success is often
coloured by many less fruitful hours. I am
pleased to tell you that the planning for the
New York City meeting is proving to have
a bit of a Midas touch about it. We have
had more abstracts submitted than ever
before for a meeting in the United States, have a cracking
programme that offers topics spanning medicine counterfeiting,
mental health therapies, and made-in-the-laboratory organs. We
have programmed the sessions so you will be absolutely spoilt by
choices when it comes to where to go and who to see, and
honestly, if the enquiries we have had are any indication of the
level of interest in our 35th Annual Meeting & Exposition, then
we expect to welcome a huge gathering of the great and the
greater to New York City. To insert one, and only one, cliché: can
you afford to miss this?
We all know that the best deals are carried out over a cardboard
cup of hot coffee, and so we have structured each day to allow for
maximum networking. This has been done by allowing for many
exhibition, as well as many more science, showcase hours, so you
can learn something new, make new contacts, and meet up with
old, and not so old, friends all under one roof! Now
CRS makes it even easier for you to select your educational
workshop, register for the annual meeting, and purchase your
banquet tickets by providing online registration.
The CRS Annual Meeting & Exposition is unique in that it is
not so large as to be absolutely overwhelming, in an “I cannot
find my colleagues” sort of way, and yet is large enough to include
a good sprinkling of scientists from the different disciplines in
our science, as well as our friendly regulators. Our size and
dedication to our members
are some of our unique
selling points.
Hilton New York. Photo by Ed Jacoby.
20
The CRS Annual Meeting
& Exposition is a meeting
that focuses exclusively on
emerging technologies.
We are passionate about
new science, and I can tell
you that the two days that
Mark Tracy, Kam Leong,
Martyn Davies, Teresa
Virgallito, and I spent
going through the
abstracts were two of the
most exciting days of 2008
Central Park. © Jeff Greenberg
for me, as the science being carried out by all of you is simply
breathtaking. Some of the abstracts left me gasping an unspoken
“why didn’t I think of that?” Pure pleasure! We had a hard job
selecting the very best for podium places. We did it in the end
though, so you will get to hear some of our top scientists tell you
about their ideas and how they validated them with good quality
data. Some of the people I am anxious to hear speak are ShyhDar Li from the University of North Carolina, who is developing
siRNA therapies for the treatment of cancer metastases, and
Valentine Wascotte from the Université Catholique de Louvain,
who is developing a non-invasive skin-based test for kidney
disease. I could go on and on about the scientists who caught my
eye, but we have limited space!
If you know of new scientists starting out who are wondering
where to pitch their tents, this is the conference for them, as our
knowledge gaps will be on display. Alternatively if you are a
seasoned scientist looking to commercialise your endeavours,
we have a healthy level of industrial attendees, in actual fact two
halls full of industry exhibitors to choose from. If you happen to
be one of a handful of thought leaders, you should attend, just to
make sure that you are still a thought leader, if you catch my
drift. Finally, if you are looking for technology to launch your
next product, there is nowhere else on earth with pharmaceutical,
consumer products technologies, and animal health all under one
roof, and we all know that “borrowing” technology from one
sector to service the other is a quick and easy way to out patent
our intellectual property rivals.
Be sure to take advantage of your membership in the CRS and
register now for the 35th CRS Annual Meeting & Exposition
and an Educational Workshop at the member rates. Remember
we want to see you and your work at the Hilton New York
July 12–16! n
See These Exhibitors at the
35th CRS Annual Meeting & Exposition
July 12–16, 2008 • New York, New York
Exhibiting companies that have reserved space at the 35th Annual Meeting and Exhibition of the
Controlled Release Society, as of press time, are listed below. For ongoing updates, visit
www.controlledreleasesociety.org/meeting/exhibitors/currentExhibitors.cfm.
3M Drug Delivery Systems
AC Compacting LLC
Adhesives Research
Aicello Chemical Co., Ltd.
Alkermes Inc.
Allergan, Inc.
Almac Group
American Pharmaceutical Review
Aptuit
Aqualon, A Business Unit of
Hercules Inc.
Asahi Kasei Chemicals
Corporation
Avanti Polar Lipids, Inc.
Avantium Technologies
Aveva Drug Delivery Systems
Azopharma
Banner
BASF Corporation
Bilcare
Bio-images Research Ltd.
Bio-Lab Ltd.
Biovail Contract Research
Boehringer Ingelheim
Brookwood Pharmaceuticals
Buchi Corporation
Capsulution NanoScience AG
Catalent Pharma Solutions
ChemAgis USA, Inc.
ChemImage Corp.
CMA/Microdialysis
Coating Place, Inc.
Colorcon
Contract Pharma
Croda Inc.
Depomed, Inc.
Dermatrends, Inc.
Dissolution Technologies
DPT Laboratories
Drug Delivery Technology
Drug Discovery Today
DSM Biomedical
Duoject Medical Systems
DURECT Corp.
Eastman Chemical Company
Elan Drug Technologies
Elsevier
Erweka America Corp.
Eurand
FormuMax Scientific
Fuji Health Science
Gattefosse Corp.
Gaylord Chemical Corp.
Genzyme Pharmaceuticals
Glatt Pharmaceutical Services
Halozyme Therapeutics
Hanson Research
Hisamitsu Pharmaceutical Co., Inc.
IMA North America Inc.
Informa Healthcare Publishers
Innocore Technologies
Intertek MSG
Irvine Pharmaceutical Services
LCI Corporation
Lipoid LLC
Logan Instruments
LTS Lohmann Therapy Systems
Lubrizol
MedTRACK
Molecular Profiles
Mylan Technologies Inc.
NAL Pharma Ltd.
Nano Imaging Services
National Adhesives
Nisco Engineering AG
Nisso America Inc.
NOF Corporation
Northern Lipids Inc.
NovaMatrix/FMC BioPolymer
Noven Pharmaceuticals, Inc.
Oakwood Laboratories
OctoPlus NV
O’Hara Technologies
ONdrugDelivery
Oxford Instruments
Patheon Inc.
Pharmaceutical Profiles Ltd.
Pharmaceutical Technology
PharmaForm
Pharma Magazine
Pharma Polymers, Evonik
Industries
Pharmatek Laboratories, Inc.
PharmCircle
Pharsight Corporation
Philips Research
PII
PolyMicrospheres-Advanced
Nanotechnologies
Polymun Scientific GmbH
PURAC Biomaterials
Rohm & Haas Company
RTS Life Science
Samedan Ltd.
Scintipharma, Inc.
Shin-Etsu Chemical Co. Ltd.
Simulations Plus, Inc.
Skin Scientifica Inc.
Soliqs
SOTAX Corporation
Southwest Research Institute
Surface Measurement Systems NA
SurModics, Inc.
Sympatec, Inc.
Technology Catalysts International
Texture Technologies
Thermo Scientific
Varian, Inc.
Vector Corporation
XSpray Microparticles
Questions?
Contact Debby Woodard, CRS Business Development
+1.651.994.3817 • [email protected]
21
What’s on Board?
What’s on Board for the Future?
Selecting just the right venue for a CRS Annual Meeting &
Exposition is something the Board of Directors takes quite
seriously. It can be a daunting task when you consider CRS has
members in more than 50 countries.
The Board and CRS headquarters staff work closely together to
choose three or four potential locations for an annual meeting
and exposition in any given year. One of the ways cities and
countries are decided upon is by hearing from you. Members who
attend an annual meeting and exposition are asked to complete
and submit a survey at the conclusion of the summer’s event. One
of the questions asked on the survey is where would you like to
see an annual meeting and exposition held? The answers are
gathered, discussed, and considered when the CRS Board and
staff are planning future meetings. The next time you’re asked
where you’d like CRS to meet, don’t be shy, let your voice be
heard, and tell your Society where you’d like to be in the future.
By using survey results, the Board and staff have learned that
CRS members like attending annual meetings and expositions in
Europe and going from one U.S. coast to the other. Because of
the diverse membership of CRS, a variety of locales are always
considered.
PRODUCTS
DRUG DELIVERY
In an attempt to balance the wishes of members and the bank
account at the same time, the CRS Board has selected the next
three annual meeting and exposition locales. They are
36th CRS Annual Meeting & Exposition
July 18–22, 2009
Copenhagen, Denmark
37th CRS Annual Meeting & Exposition
July 10–14, 2010
Oregon Convention Center
Portland, Oregon U.S.A.
38th CRS Annual Meeting & Exposition
July 30–August 3, 2011
Gaylord National Resort and Convention Center
National Harbor, Maryland U.S.A.
These areas of the world were suggested by you, the members
of the CRS, so we certainly hope to see you at each place when
their time comes for the next CRS Annual Meeting &
Exposition. Thank you for expressing yourselves! n
CONTRACT DEVELOPMENT
Join our workshop!
Sunday, July 13, 10.30 AM, room Sutton North
Controlled release technologies for the delivery
of protein therapeutics
Attend our presentation and join the discussion on:
+ The opportunities and challenges of controlled release drug
delivery technologies for protein delivery
+ Formulation aspects and analytics of encapsulated proteins
+ The application of biodegradable polymers for the development
of single-shot vaccine delivery
This workshop is open for all registered attendees, especially for scientists
and business development professionals interested in controlled release of
large molecules for improved delivery or line extensions
22
PHARMACEUTICAL
INNOVATORS
OctoPlus
Zernikedreef 12
2333 CL Leiden, the Netherlands
Telephone +31(0)71 524 40 44
Fax +31(0)71 524 40 43
www.octoplus.nl
Patent Watch
Transdermal Update 2008
Priya Batheja,1 Agis Kydonieus,2 Diksha Kaushik,1 and Bozena Michniak-Kohn1
We searched the literature for patents and patent applications
related to transdermal delivery published during the calendar
year 2007 and uncovered 288 such publications. Of these, 33
were issued US patents and 86 were US patent applications.
There were also 83 World (WO), 72 European (EP), and 14
Japanese patent publications. It should be noted that many of
these patents are counted more than once, since a patent
application can be filed in the US, WO, and EP patent systems
at the same time.
In this update we have reviewed mainly the US issued patents.
Of the 33 issued patents, 10 pertained to electromechanically
enhanced delivery and 23 to passive diffusion, including 8 for
chemical enhancement. Some of the most pertinent publications
and interesting highlights of this market are summarized below.
In September 2007 the FDA granted approval to Novartis for
the Exelon patch containing rivastigmine, for the treatment of
Alzheimer’s disease. The patch can be applied to the back, chest,
or upper arm and delivers 9.5 mg of rivastigmine over a period
of 24 hr. Rivastigmine is a cholinesterase inhibitor that increases
the activity of the neurotransmitter acetylcholine in the brain.
The patch has been shown to reduce side effects such as nausea,
vomiting, and other gastrointestinal side effects that are
prevalent with the capsule form of the drug.
Separately, U.S. scientists at the University of South Florida have
announced the development of a transdermal vaccine for
Alzheimer’s disease, which triggers the immune system to clear
amyloid beta, a protein found in abnormal quantities in the
brains of Alzheimer’s patients.
In July the FDA also approved a spray developed by Acrux for
the treatment of post-menopausal vasomotor symptoms such as
hot flashes. The spray is a fast-drying formulation (45 sec)
containing a naturally occurring estrogen (estradiol), an
enhancing substance derived from sunscreen extract and a
volatile solvent. The spray is applied to the inner forearm and it
absorbed into the blood over a 24-hr period on a sustained basis.
The product will be marketed in the United States by KV
Pharmaceuticals.
Mylan also obtained approval for its generic fentanyl patch,
which delivers 12 µg of fentanyl per hour. Mylan offers all five
strengths of transdermal fentanyl, which is the generic version of
Alza’s Duragesic patch. During 2007, Lavipharm also obtained
approval for its fentanyl generic patch.
Laboratory for Drug Delivery, Rutgers-The State University of
New Jersey, NJ, U.S.A.
2
Samos Pharmaceuticals, LLC, Kendell Park, NJ, U.S.A.
1
In other developments, both Altea Therapeutics and
Phosphagenics Ltd. have announced positive results for Phase I
human studies with their topical insulin products. Altea is
developing 12- and 24-hr transdermal patches to provide
constant basal levels of insulin for people with type 1 or type 2
diabetes. In other Phase I developments, Transpharma Medical
has announced positive results for the transdermal delivery of
hPTH (human parathyroid hormone) for the treatment of
osteoporosis. The 48-subject study was conducted to compare the
tolerability and pharmacokinetics of hPTH patches to FORTEO
(Teriparatide) (Eli Lilly) administered subcutaneously. Chrono
Therapeutics also has announced positive results for their Phase I
trial with their pulsative transdermal drug/device combination.
The dose escalation trial showed statistically significant
modulation and control of the dosing profiles. Finally, Acrux and
Organon have announced a collaboration to develop and
commercialize contraceptives, using Acrux’s unique spray
technology.
PASSIVE DIFFUSION
Methods and Devices for Transdermal Delivery
Abuse-Resistant Transdermal Dosage Form (3M
Innovative Properties Company) US 7182955
A transdermal drug delivery device is described, where the device
is capable of preventing abuse or misuse of substances such as
narcotics or other agents. The active agent is present in a
polymeric material that is in contact with the skin surface and
may also contain additives such as penetration enhancers,
antioxidants, etc. A barrier layer is present between the active
reservoir and an adverse agent reservoir, which contains an
antagonist to the active. On its other side, the adverse agent
reservoir is connected to a porous medium that is in “fluid
communication” with the proximal side of the active agent
reservoir in contact with the skin. The antagonist is not delivered
to the skin surface at a therapeutic level during intended use, but
during attempted abuse, such as contact of the active agent with
a liquid or its immersion in a liquid, the liquid also flows to the
porous material, leading to release of the antagonist from the
dosage form along with the abusable drug substance, thus
preventing intended abuse.
Compositions and Methods for Transdermal Oxybutynin
Therapy (Watson Pharmaceuticals, Inc) US 7179483
The present invention discloses methods and compositions for
administration of oxybutynin, an anticholinergic used for
treatment of overactive bladder and urinary incontinence, in ways
that minimize associated adverse drug experiences such as dry
mouth, dizziness, blurred vision, and constipation. The adverse
effects are generally attributed to the presence and amount of
active metabolites of oxybutynin, such as N-desethyloxybutynin,
Transdermal Update 2008 continued on page 24
23
Transdermal Update 2008 continued from page 23
and are observed in a large number of patients to an extent that
leads to treatment discontinuation. Embodiments of the
invention include transdermal and topical dosage forms that
specifically encompass each isomer for both oxybutynin and its
corresponding metabolites, such that on administration the ratio
of area under the plasma concentration-time curve (AUC) of
oxybutynin to an oxybutynin metabolite is about 0.5:1 to about
5:1. The transdermal formulation may include permeation
enhancers, anti-irritants, adhesion adjusters, and combinations
thereof and has been shown to lower the mean AUC ratio of
(R)-N-desethyloxybutynin to (R)-oxybutynin, resulting in
greatly reduced amounts of the active metabolites of oxybutynin,
while providing a therapeutically effective amount of oxybutynin.
These formulations thus provide a significant advantage over oral
administration of oxybutynin.
Drug Delivery System for Implantable Cardiac Device
(Cardiac Pacemakers, Inc.) US 7201733
A responsive transdermal drug delivery system that can be
incorporated into a cardiac device and can deliver the dose upon
detection of a particular medical condition is disclosed. The
implantable cardiac device, such as a cardiac pacemaker or
defibrillator, can sense electrical activity occurring in a patient’s
heart and generate sensing signals that indicate the activity, such
as arrhythmia or ischemia. With the help of a telemetry
interface, the device can transmit radio frequency signals to the
drug delivery device, which can be an electrically modulated
transdermal drug delivery device affixed to the patient’s skin. The
drug delivery device consists of a microprocessor, memory, and a
telemetry interface for receiving and demodulating radio signals
received from the cardiac device. On receipt of the signals, it can
deliver a pre-programmed quantity of the drug in a specific time
period, leading to controlled drug delivery. The system can also
be programmed to maintain a downloadable log of the sensed
physiological variable and the amount of drug delivered by the
device, which can provide feedback that can be used to formulate
an optimum drug dosage schedule for the patient.
System and Method for Optimizing Tissue Barrier
Transfer of Compounds (Transform Pharmaceuticals, Inc.)
US 7172859
The present invention relates to high-throughput systems and
methods to prepare a large number of single- or multiplecomponent formulation combinations at the same time and
high-throughput methods to test the tissue (skin) transfer of
such combinations. An embodiment of the invention describes
an apparatus comprising a support plate, an array of samples on
the plate, a membrane/tissue overlaying the array of samples, and
a reservoir plate secured to a side of the membrane opposite the
array of samples. The combinatorial high-throughput apparatus
can be used to prepare and load samples, overlay the array of
samples with a tissue specimen, secure the upper reservoir plate
corresponding to the array of samples and fill them with a
reservoir medium, and finally measure the concentration of each
reservoir as a function of time to determine the flux of the actives
across the membrane. Another embodiment of the invention also
describes the ability to cut the tissue specimen to avoid lateral
24
diffusion between wells and analyze the tissue specimen for
defects or inhomogeneities. In addition, the system can also aid
in processing samples by stirring, milling, filtering, centrifuging,
emulsifying, lyophilizing, and reconstituting prior to assembly of
the entire apparatus. The system typically can analyze at least 10
samples, and preferably more than 1,000 samples.
Transdermal Drug Delivery Device (Alza Corporation) US
RE39588
A controlled release transdermal device for delivery of therapeutic
agents is disclosed, whereby the device can provide diffusional
drug delivery that prevents an initial burst of the drug, thus
causing less irritation and providing delayed onset of drug
administration. The delayed release is particularly beneficial in
delivering drugs that have a tendency to irritate skin in large
doses, such as benztropine, nicotine, and propranolol. The
invention also claims a delivery device in which the therapeutic
agent is converted from the stable form suitable for storage to the
form suitable for delivery through the skin after the device is
placed into its environment of use (in contact with the skin or
mucosa). When placed in a biological environment, the moisture
migrates into the system from the skin surface by osmosis or
diffusion and passes through the adhesive layer and then to the
activating means, where it mixes with an activating agent,
preferably an acid or base stored in its anhydrous form. The acid
or base forms an acidic or basic solution with the water, migrates
into the salt drug reservoir, and converts the salt drug to its free
form, which then passes freely through device layers and then
through the skin. This invention has particular utility for the
delivery of drugs that have a tendency to be unstable in their
active forms but that are more stable as salts (sympathomimetic
drugs such as terbutaline, salbutamol, and ephedrine). The device
can also incorporate a rate-controlling membrane present
between the activating agent and the drug reservoir that can serve
to control the rate of hydration and diffusion of the activating
agent, thereby controlling the delivery of the active drug.
A Method of Transdermal Drug Delivery Using Hyaluronic
Acid Nanoparticles (University of South Florida) US
Patent Application 20070036728
A method for the development of hyaluronic acid (HA)
nanoparticles is presented, which is useful for the transdermal
delivery of macromolecules, such as peptides, DNA, and other
hydrophilic or hydrophobic molecules. The method of
preparation of the HA nanoparticles comprises the steps of
mixing HA and a hydrazide (oxalic acid) with a crosslinking
agent (carbodiimide) in an aqueous solution, adding a non-polar
organic solvent and a surfactant (sorbitan monostearate) to form
an oil-in-water emulsion, and lowering the pH to allow
intermolecular and intramolecular crosslinking. The nanoparticles
are precipitated by the addition of alcohol.
Formulations for Amylin Agonist Peptides (Amylin
Pharmaceuticals) US 7312196
A liquid pharmaceutical formulation is provided that comprises
about 0.5–1.0% of an amylin peptide agonist, a buffer, a tonicifier
or stabilizer, and a preservative. The formulation can be in liquid,
gel, or powdered form for delivery by several means, including
transdermal drug delivery.
Enhancers for Transdermal Delivery
Composition for Transdermal and/or Transmucosal
Administration of Active Compounds that Ensure
Adequate Therapeutic Levels (Antares Pharma IPL AG)
US 7214381
A pharmaceutical composition for transdermal and/or
transmucosal delivery of diverse therapeutic agents via a gel or
solution dosage form is disclosed. This system claims to have the
potential for sustained and controlled delivery of actives ranging
from hormones to other agents such as sedatives, anxiolytics,
antihypertensive agents, and calcium regulators. This
transdermal/transmucosal formulation entails a novel
combination of various penetration enhancers that include 1)
saturated fatty alcohols, saturated fatty acids, unsaturated fatty
alcohols, and unsaturated fatty acids of formulae CH3(CH2)
-CH2OH, CH3(CH2)n-CH2COOH, CH3(CnH2(n–1))OH, and
n
CH3(CnH2(n–1))COOH, respectively, wherein n is an integer
between 8/22; 2) a ternary vehicle consisting of a C1/C4 alkanol,
a polyalcohol, propylene glycol, and water; and 3)
monoalkylether of diethyleneglycol. When the specific
combination of lauryl alcohol and diethylene glycol monoethyl
ether (Transcutol.RTM.P) are used to enhance composition, an
adequate penetration enhancement factor and a sustained flux of
the active agent is attained, thereby providing therapeutic,
effective, controlled, and sustained levels of the active drugs by
only once-a-day application of the formulation.
Drug Delivery Method by Enhanced Topical Application
(CeramOptec Industries Inc.), US Patent Application
20070154536
A method of enhancing delivery of actives into human/animals
via hair follicles is claimed that employs the use of a swellable
formulation constituting biodegradable and bioactive polymers
encapsulated in the form of microspheres or liposomes. The
formulation is designed in such a way that it maintains the
passage of actives by either 1) opening hair follicles and
preventing them from collapsing; or 2) increasing the depth of
the inner lumen of the hair follicles. This method claims to
improve the flux of actives via hair follicles, causing localization
of active in the tissues surrounding the hair follicles or under the
skin and thereby leading to systemic delivery without skin surface
modification. This novel system offers the advantage of increasing
therapeutic effects of actives in the treatment of skin disorders
and can also help in permanent removal of unwanted hair.
Mixture of Delivery of Low and High Molecular Weight
Compounds (JRX Biotechnology, Inc.) US 7201919, US
7220427, US 7300666
A transdermal delivery system has been disclosed that is capable
of delivering high molecular weight pharmaceuticals and
cosmetic agents to the skin. This system comprises mainly three
components: penetration enhancer, aqueous adjuvant, and an
active. The penetration enhancer is a mixture of hydrophobic and
hydrophilic domains, with the hydrophobic domain mainly
containing animal- or plant-derived ethoxylated lipids and the
hydrophilic domain ranging from alcohols to non-ionic
solubilizers or emulsifiers. The aqueous adjuvants used in this
system are water, Aloe vera juice, or other plant extracts. The
therapeutic or cosmetic actives delivered through this system can
consist of not only low molecular weight compounds such as
NSAIDS (non steroidal anti-inflammatory drugs), capsaicin,
boswellin, and antiviral compounds, but also extend to
transdermal delivery of high molecular weight agents like
collagen.
Penetration Enhancing and Irritation Reducing Systems
(Cellegy Pharmaceuticals Inc.) US 7157097
A system capable of percutaneous enhancement of an active
(preferably estradiol and its derivatives) is divulged, with the
additional advantage of reducing the irritation associated with its
transdermal or topical delivery. The formulation includes a
therapeutic agent, a penetration-enhancing system, and a gelling
agent and is maintained at a pH of 4–8. The pharmaceutical
composition can vary from solutions, lotions, creams, and
ointments to gels, aerosols, and patch devices. The penetrationenhancing system in this formulation is composed of a mixture
of three components, namely a membrane fluidizer (oleic acid), a
C1–C4 alcohol (ethanol, propanol, isoproponal, or their mixtures),
and a penetration-enhancing alcohol (ethylene glycol, propylene
glycol, butylene glycol, or their mixtures). The gelling agent
incorporated in the formulation is usually selected from a group
consisting of Carbopol® 1342, Carbopol® 940, Klucel®, and
Klucel® HF. In addition to transdermal delivery, this system
claims to possess mucosal penetration-enhancing effects.
Transdermal Administration of Nonsteroidal Antiinflammatory Drugs Using Hydroxide-Releasing Agents as
Permeation Enhancers (Dermatrends, Inc.) US 7244447
A method for enhancing the transdermal delivery of nonsteroidal
anti-inflammatory drugs via a system involving hydroxidereleasing agents as a permeation enhancer is proclaimed. The
formulation in this system is composed of a nonsteroidal antiinflammatory agent, a hydroxide releasing agent, and a
pharmaceutically acceptable carrier and can be prepared in
several dosage forms, such as liquid, semisolid, or transdermal
patch. The NSAID used in the formulation is a propionic acid
derivative that is absorbed systemically upon transdermal
delivery. The hydroxide releasing agent is an inorganic hydroxide
such as sodium hydroxide or potassium hydroxide that releases
free hydroxide ions in the presence of an aqueous carrier and
subsequently improves the flux of the NSAID. The aqueous
carrier may be natural moisture present at the skin surface or
water accumulated due to the occlusive backing of the patch
form. The method claims to minimize the probability of skin
damage, irritation or sensitization associated with the application
of the active and also shows suitability in enhancing the flux of
NSAIDs across mucosal tissue.
Transdermal Update 2008 continued on page 26
25
Transdermal Update 2008 continued from page 25
ELECTROMECHANICALLY ENHANCED DELIVERY
Compositions for Electroporation (Pola Chemical
Industries Inc.) US 7197359
A method for increasing percutaneous absorption is claimed that
comprises composition of a drug, an electrolyte, and 5–0% of a
polyhydric alcohol and menthol. The concentration of the drug
to the electrolyte is adjusted so the osmotic pressure of the
composition is lower than the osmotic pressure of physiologic
saline, thereby elevating percutaneous absorption. The
composition is applied to the skin, and voltage is applied by an
electroporation device for a short period of time. The
percutaneous absorption is enhanced for the remaining time of
the treatment without further application of voltage. Propylene
glycol is claimed as the polyhydric alcohol, and the optimum
applied voltage is 300 V at a capacitance of 25 µF for 5 min.
Device for Enhanced Delivery of Biologically Active
Substances (Intrabrain International NV) US 7200432
A method is described for the non-invasive transnasal or
transocular iontophoretic delivery of a drug to the central
nervous system (CNS) in an enhanced fashion and bypassing the
blood brain barrier. The method comprises the following steps:
1) supplying the drug formulation proximate to the target region;
2) establishing an iontophoretic energy gradient between the
drug supply and the target tissue; and 3) delivering the drug
directly to and through a nervous system pathway to the target
site without transiting through skin layers and vasculature, thus
delivering the drug at higher rates.
Device for Transdermal Electrotransport Delivery of
Fentanyl and Sufentanil (Alza Corporation) US 7302293
An iontophoretic device is described that comprises a switch
that activates the device to deliver a dose of about 20–60 µg of
fentanyl for a predetermined period of up to 20 min and then
terminate said delivery. The iontophoretic control circuit allows
up to 100 additional doses over a period of a day. The delivery
of fentanyl and sufentanil is sufficient to induce analgesia in a
human patient suffering from moderate to severe pain associated
with major surgical procedures.
Methods of Monitoring Glucose Levels in a Subject and
Uses Thereof (Animas Technologies, LLC) US 7228163
A method is presented for monitoring the effect of a
pharmaceutical composition, such as one comprising
pentamidine, saquinavir, quinine, or indomethacin, on the
glucose levels of a subject receiving such a pharmaceutical
composition. The method comprises the following steps:
1) iontophoretically extracting a glucose sample from the subject;
2) bringing the sample in contact with a sensor in the presence
of glucose oxidase that reacts with glucose to produce hydrogen
peroxide; 3) detecting and measuring hydrogen peroxide, which
is specifically related to the concentration of glucose in the
subject; and 4) comparing the glucose concentration values to the
record of treatments with the pharmaceutical composition.
26
Transdermal or Transmucosal Drug Delivery Device
(Hisamitsu Pharmaceutical Co. Inc.) US 7200433
An iontophoretic transdermal or transmucosal delivery device is
disclosed in which an energy pattern controller is configured to
enable the drug delivery device to provide energy through 1) a
combination of a pulse-depolarized type and a direct current and
pulse type; 2) the pulse-depolarized type supplying repetitive
pulses and discharging a residual charge during a pulse resting
period; and 3) the pulse type supplying repetitive pulses, wherein
the types of energization are conducted sequentially. It is claimed
that the device gives excellent drug permeability with low
irritation and reduced power consumption.
Device for Manipulating a Needle or Abrader Array and
Method of Use (Becton Dickinson and Company) US
7186235
A microneedle device and a method for delivery of a drug are
disclosed that comprise 1) a bottom wall having a planar outer
surface with a plurality of 10-µm to 1.5-mm microneedles
extending outward and having a length of 100–250 µm; 2) side
walls and a top wall defining a reservoir for said substance to be
delivered; 3) a device-manipulating member that is deformable
and attached to at least one wall and extending beyond said wall;
and 4) the manipulating member is a handle allowing one to
hold the device and apply pressure on at least one of the walls to
dispense said substance from the reservoir. It is claimed that the
device avoids or eliminates excess pain and discomfort normally
caused as a result of microbraders or microneedles entering the
epithelial layers beneath the stratum corneum.
Functionalized Microneedle Transdermal Drug Delivery
Systems, Devices and Methods (Gregory A Smith) US
Patent Application 20070078376
Iontophoretic devices and methods are disclosed for
transdermally delivering therapeutically active agents through an
array of microneedles. The method provides for microneedles
formed on a substrate, said substrate, and needles being
functionalized with functional groups such as alkoxysilanes.
Optionally, an iontophoretic assembly is provided in which the
active electrode assembly comprises an active agent reservoir
wherein the surface-functionalized substrate is positioned
between the active electrode assembly and the skin.
Microneedle Drug Delivery Device (Georgia Tech
Research Corporation) US 7226439
A simple device with a plurality of hollow microneedles is
provided that allows delivery of drugs at clinically effective rates,
with minimal damage, pain, or irritation to the tissue. The device
comprises a substrate to which the plurality of microneedles is
attached and a reservoir containing the drug, which is in
communication with the microneedles. The reservoir can be
made of deformable elastic material, so the amount of drug
delivered can be selectively altered by compressing the reservoir.
The reservoir can also be a syringe or a pump connected to the
substrate.
Interface for Transdermal Drug Administration Device
(Hirotoshi Adachi et al.) US Patent Application
20070123837
A microneedle transdermal delivery device is provided that can
apply a drug to the skin evenly from a plurality of projections
through the skin. The device comprises a flat plate with a
plurality of two dimensionally arranged conical or pyramidal
projections and a plurality of openings capable of delivering the
drug, which are respectively arranged in correspondence with the
projections. The flat plate can be made of metal or ceramic, and
the ratio of the openings to the projections can be 1:1 to 1:2,
respectively.
Devices for Transcutaneous Delivery of Vaccines and
Transdermal Delivery of Drugs and Uses Thereof (Iomai
Corporation) US Patent Application 20070088248
A system for disrupting the skin is disclosed that comprises a
mask and a disrupting member mechanically coupled to the
mask, wherein said mask has an opening and it contains a
fastener (PSA) to secure the mask to the skin and said
disrupting member is capable of being passed over the opening
to disrupt the exposed skin. The disrupting member can be a
metal or a ceramic abrasive made up of metal blades or
protrusions capable of cutting grooves in the skin.
Macromolecules, including antigens and vaccines, can be
delivered through the disrupted skin area.
Intradermal Incorporation of Microparticles Containing
Encapsulated Drugs Using Low Frequency Ultrasound
(Ultra-Sonic Technologies, LLC) US 7232431
An apparatus and method of sonoporation of the skin are
disclosed for the intradermal delivery of a microparticle
suspension. The microparticles can have a diameter of 0.1 to 50
µm and can be liposomes, polymeric spheres, and biodegradable
particles. The tip of an ultrasound horn applies ultrasound
radiation to the microparticle suspension to generate cavitation
bubbles, causing pores to be formed in the skin of the patient.
The ultrasound radiation (1–30 kHz) intensity and distance from
the skin are also effective in forming ultrasonic jets driving the
microparticles through the formed pores into the skin. The
ultrasound radiation is applied at a frequency other than the
resonant frequency of the microparticles to avoid rupturing
them. n
27
People in the News
Compiled by Steven Giannos
Industrial Editor
Profs. Patrick Stayton and Allan Hoffman Start PhaseRx, a
New Seattle Biotech Company Formed for Delivery of
siRNA and Other Macromolecules
PhaseRx Inc. is a new Seattle biotechnology startup company
focused on developing novel approaches to the delivery of
siRNA and other macromolecules. On February 28, 2008, they
announced the closing of their initial institutional financing,
totaling $19 million. The financing was led by ARCH Venture
Partners, 5AM Ventures, and Versant Ventures.
PhaseRx was formed by Robert Overell of Foundation
BioVentures together with co-founders Profs. Patrick Stayton
and Allan Hoffman from the University of Washington’s
Department of Bioengineering; Prof. Oliver Press, MD, of the
Fred Hutchinson Cancer Research Center’s Clinical Research
Division; and Dr. Paul H. Johnson, the company’s chief scientific
officer. The company has exclusively licensed novel polymer
technology from the University of Washington that was
developed by the Stayton and Hoffman laboratories, in
collaboration with the Press laboratory. This technology enables
the effective intracellular delivery of siRNA. Pat Stayton and
Allan Hoffman are long-time members of the Controlled
Release Society. Hoffman received the CRS Founders Award in
2007.
Altea Therapeutics Appoints Dr. Richard H. Guy to Its
Scientific Advisory Board
Business Wire: February 13, 2008 – ATLANTA, Ga. – Altea
Therapeutics has announced that Dr. Richard Guy, professor of
pharmaceutical sciences and the head of the Department of
Pharmacy & Pharmacology at the University of Bath, has joined
the company’s Scientific Advisory Board.
“Richard Guy is a leading scholar in the field of transdermal
drug delivery. We are thrilled to welcome him as a member of
our scientific advisory board and look forward to his close
association with our scientists as we develop our proprietary
transdermal patch technology, the PassPort System, designed for
the efficient delivery of drugs that normally would need to be
administered by needle injection, including proteins,
carbohydrates and water-soluble drug salts,” said Dr. Eric
Tomlinson, president and CEO for Altea Therapeutics.
“Altea Therapeutics has recently made several significant
advances in the transdermal delivery field,” said Prof. Guy, who
added “The PassPort Transdermal Delivery System has the
potential to expand the classes of drugs that can be painlessly
delivered from a skin patch. I look forward to working with the
scientific team at the company.”
28
Dr. Guy’s principal scientific achievements are in the areas of
characterizing the function of the skin barrier for drug
absorption, enhancement of percutaneous absorption,
iontophoresis, noninvasive bio-sensing of blood glucose and
other analytes, and the prediction and assessment of skin
penetration and topical bioavailability. Dr. Guy has published
more than 250 peer-reviewed articles and more than 70 book
chapters and has co-authored one book and co-edited seven
others. He is also a co-inventor on 10 patents. Dr. Guy received a
M.A. degree in chemistry from Oxford University and a Ph.D.
degree in pharmaceutical chemistry from the University of
London. He has held academic posts at the University of
California, San Francisco and the University of Geneva. Dr. Guy
serves on the editorial advisory boards of numerous journals,
including the European Journal of Pharmaceutics and
Biopharmaceutics and Diabetes Technology & Therapeutics. He is a
past president of the Controlled Release Society and is an
advisor to several companies in the pharmaceutical, cosmetic, and
biotechnology industries. Dr. Guy is an elected Fellow of the
Academy of Pharmaceutical Scientists, Great Britain, the Royal
Society of Chemistry, the American Association of
Pharmaceutical Scientists, and the American Association for the
Advancement of Science.
David W. Grainger Joins Drug Delivery Journal as
Co-editor-in-Chief
PRNewswire: January 22, 2008 – NEW YORK, N.Y. – David
W. Grainger, Ph.D., has joined the Drug Delivery Journal as Coeditor-in-Chief. Drug Delivery, published by Informa
Healthcare, a leading content provider of pharmaceutical science
information for the academic and industrial communities with
peer reviewed coverage of basic research, development, and
application principles at molecular, cellular, and higher levels.
Dr. Grainger, currently professor and chair of the Department of
Pharmaceutics and Pharmaceutical Chemistry in the College of
Pharmacy at the University of Utah, is an internationally
respected and award-winning professor and scholar in the drug
delivery and biomedical device fields. His new appointment
seeks to guide the journal’s overall direction within the drug
delivery community as this field evolves and integrates with
emerging science and technology. It also signals an invitation for
new high-quality manuscripts now being accepted for
consideration for publication in Drug Delivery.
“Dr. Grainger’s new position as Co-editor-in-Chief of Drug
Delivery signifies an exciting new direction for us,” says Carolyn
Honour, vice president and publishing director, Informa
Healthcare, Pharmaceutical Science. “Dr. Grainger’s expertise
offers a fresh perspective on current research and development[s]
in this area and should establish a new era of leadership for a
journal that carries a tradition of delivering quality articles to the
scientific community.” Drug Delivery publishes original research,
critical reviews, book reviews, and industry announcements, such
as patent updates, literature alerts, and news of important events.
“I’m really excited and challenged about my new role at Drug
Delivery,” declares Dr. Grainger. “I’m looking forward to
attracting, acquiring-and publishing-the highest quality and
most impacting research articles to help advance and disseminate
the work being done in this field.”
Dr. Grainger, a past member of the Scientific Advisory Board
and annual symposium chair for the Controlled Release Society,
holds many advisory panel positions within the industry. Among
the many honors he has received is the PhRMA Foundation’s
Excellence in Pharmaceutics Award (2005) and the Society for
Biomaterials’ Clemson Award for Basic Research in Biomaterials
(2007). He earned his Ph.D. degree in pharmaceutical chemistry
from University of Utah. n
Renew for 2008!
As a Member You Receive
Discounts
Contact CRS Headquarters Today
+1.651.454.7250
Already a member?
Encourage your colleagues to join.
•Annual Meeting & Exposition member rates
•Annual Meeting & Exposition symposia Transactions
on CD-Rom
•Subscription to the quarterly CRS Newsletter
FREE
•Significantly reduced subscription rates
to the
•Journal of Controlled Release
•European Journal of Pharmaceutics and
Biopharmaceutics
•Biomaterials
Industry Connections
•Online membership directory
•Online job placement service
•Volunteering and leadership opportunities
Opportunities to Be Involved
•Volunteer on a committee
•Organize an Educational Workshop or Satellite
Meeting
•Present an abstract
•Join a Local Chapter
•Submit a book proposal
•Review abstracts
www.controlledreleasesociety.org
29
Welcome New Members
Mohammad J.
Abdekhodaie
Tiffany S. Adams
Prafulla Agrawala
Remigius U. Agu
Denize Ainbinder
Adam W. G. Alani
Courtney Anderson
Samantha N. Andrews
Shabbir Anik
Yasutaka Anraku
Elias M. Assaad
Rania M. Badr
Misuk Bae
Lisa M. Bareford
Bhavesh Barot
Guillaume Bastiat
Nicolas Bertrand
Sarah M. Betterman
Shrikant A. Bhonsle
David Blaser
Miriam Breunig
Luis Brito
David Brown
Aneta J. Brud
Vanessa Bunjes
Alexander Burghardt
Fulden Buyukozturk
Gerard D. Byrne
Gregoire Cardoen
Camilla Cervin
Prerona Chakravarty
Tamim Chalati
Lipika Chatterjee
Abhishek Chaudhary
Jun Chen
Weiliam Chen
Xiaoming Chen
Ji Cheng
Peiwen Cheng
Vinay Chhatre
Chiao-Hsi Chiang
Youngil Cho
Ji S. Choi
Leonard Y. Chu
Judith Cohen
Gemma Coombs
Philippe Couckuyt, Sr.
David C. Coughlan
John Cowley
Yen Cu
Pieter R. Cullis
Dongmei Cun
Bolivar Damasceno
Nilanjana Das
Elise Dauphin
Elisangela A. De
Moura Mendonca
IV
30
Edward DiAntonio
Thomas A. Diezi
Priscila M. D’Mello
Fred Donelson
Rakesh Dontireddy
Gerard G. M. D’Souza
Dominique Duchene
Gulengul Duman
Paul S. Egee
Hoda M. Elgendy
Mahmoud Elsabahy
Christine A. Falabella
Yassin Farag
Ryan D. Fell
Richard E. J. Forster
Todd P. Foster
Madurai G. Ganesan
Jessica Garbern
Sonia Gervais
Sarah L. Goh
Gaurav Goyal
Jacob Grunwald
Xiaochen Gu
Sevgi Gungor
Qiongyu Guo
Jyoti Gupta
Raghavendra Gupta
Vivek Gupta
Neslihan Gürsoy
Manhee Han
Oshrat Harush-Frenkel
Simon Heuking
Peter T. Higuchi
Martin Holzer
Dave Horton
Md. Sharif Hossain
Melissa D. Howard
Yi-Ling Huang
Jeesun Hwang
Lim Hyun Ju
Tomoko Ida
Annabel Igonin
Michael Jay
Steven Jay
James G. Jin
Markus Johnsson
Lene Jorgensen
Reena Joseph
Alexandra P. Kafka
Praveen Kandi
Nobuya Kaneko
Johanna Kanzer
Takeshi Kasuya
Yurie Katayama
Erik Kaunisto
Diksha Kaushik
Rizwan Kazmi
Catherine A. Kelly
Hanieh Khalili
Elena Khazanov
Jae D. Kim
Jongoh Kim
Akihiro Kishimura
Szymon Kobierski
Iryna Kravchenko
Sarah Kuechler
Neeraj Kumar
Masanori Kuramoto
Aikaterini Lalatsa
Les L. Lawrence
Jang W. Lee
Moonseok Lee
Mirko Leonhardt
Jian-Xin Li
Jinjiang Li
Ming Li
Ning Li
Hsiang-Fa Liang
Charlie Lin
Hung-Yin Lin
Wen J. Lin
Yuh-Jing Lin
Anthony Listro
Julian B. Lo
Michiel Lodder
Xiuling Lu
Steven MacLellan
Madhu Madan
Claire E. MaddenSmith
Srinivas Madduri
Karla E. Madrigal
Parth D. Mair
Vincent Malaterre
Kuldip R. Malhotra
Radhakrishna K.
Maroju
Enrico Mastrobattista
Saori Matsushita
Paul Mawson
Jaroslaw Mazgalski
Clare McCoy
Colin McCoy
Christopher W.
McDaniel
Joseph McGonigle
Ángel E. MercadoPagán
Gioconda Millotti
Masafumi Misaki
Ritu Mishra
Kanjiro Miyata
Erwin Mombarg
Cheol Moon
Jeffrey W. Moore
Stephanie J. Mudd
Claudia Mueller
Tatsuya Murakami
Yuki Murase
Narasimha S. Murthy
Senthil Murugappan
Susanne Muschert
Julien Namur
Charlene Ng
Hemin Nie
Akihiro Nishi
Kayoko Niwata
Adwoa Nornoo
Kevin P. Nott
Mohamed M. I.
Nounou
Makoto Oba
Katsuyuki Okubo
Tomoyuki Omura
Martin O’Neill
Mohammad Othman
Dawn L. Padfield
Susanne Page
Safak Paker-Leggs
Jayanth Panyam
Punit Parejiya
Hyoun-Hyang Park
Fathima Patel
Sanjay Patel
Sarsvatkumar B. Patel
Elizabeth Pearson
Chiranjeevi Peetla
Cary Percy
Glen Perera
Diana Peykova
Pemakorn
Pitukmanorom
Veronique Preat
Samuel R. Pygall
Ronny Reinberg
Zhongxu Ren
Shakila B. Rizwan
Qian Ru
Duangkamon
Sakloetsakun
Rajesh Salkar
Henelyta Santos
Ribeiro
Jennifer L. Sarafolean
Mark Saunders
Michalakis Savva
Andrew J. Sawyer
Nanette Schulte
Curtis Schwartz
Manali Shah
Milin N. Shah
Alireza Shalviri
V. Prasad R. Shastri
John N. Shell
Margarita Shumilov
John Simons
Skuli Skulason
Sohee Son
Matthew E. Staymates
Alina Stefanache
Magdalena Stevanovic
Kinjal Suchak
Hiroshi Suzuki
Deborah Sweet
Janos Szamosi
Seiichi Tada
Hikaru Taira
Nakanishi Takeshi
Dov Tamarkin
Jiansheng Tang
Chandan M. Thomas
Potta Thrimoorthy
Fredrik Tiberg
Sandip B. Tiwari
Tu Hao Tran
Ya Tsz A. Turner
Frank Van de
Manakker
Sunil Vandse
Albert Van Hell
Maria D. Veiga
Bhavna Verma
Anja Vetter
Ana Vila
Stephan G. Von
EggelkrautGottanka
Nagesh A. Wagdare
Anne J. Wandrey
Lin Wang
Yuhua Wang
Rob Ward
Alan L. Weiner
Xiaoguang Wen
Charlotte C. Williams
Hywel D. Williams
David Woolfson
Shy C. Wuang
Yuanyuan Xie
Peisheng Xu
Yoshihito Yaginuma
Motoo Yamasaki
Bruce Yan
Tatsunobu Yoshioka
Jerry C. Zhang
Wen Zhang
Mingxing Zhou
Ting Zhu
Christian Zimmer
Fatema Zohra
Hadasa Zuckerman
t"306/%5)&(-0#&t"306/%5)&(-0#&t"306/%5)&(-0#&t"306
In the News
Compiled by Steven Giannos
Industrial Editor
MAY 2008
Investigators at University of Iceland, Faculty of
Pharmacy, Publish New Data
Drug Week via NewsEdge (NewsRx.com): May 8, 2008 – A
report, “Topical Drug Delivery to the Posterior Segment of the
Eye: Anatomical and Physiological Considerations,” has been
recently published in Pharmazie. According to recent research
from Iceland, “Drug delivery to the posterior segment of the eye
is important for potentially treating various disorders in the
retina, choroid, vitreous humor and optic nerves. Due to
anatomic membrane barriers and the lacrimal drainage it can be
quite challenging to obtain therapeutic drug concentrations in the
posterior parts of the eye after topical drug administration.”
“Since the membrane barriers cannot be altered with noninvasive methods invasive methods such as direct drug injection
into the vitreous humor and subconjunctival, subtenons capsule
or suprascleral injections are gaining popularity. However,
invasive methods can cause discomfort for the patient and can
also lead to complications that are even more serious than the
disease being treated. Alternatively, novel ophthalmic
formulations can be developed that specifically target topical
drug delivery to the posterior segment of the eye. Anatomical
and physiological barriers in the eye are reviewed as well as the
theoretical model of passive drug diffusion from the eye surface
into the eye. It is shown that enhanced drug delivery through
conjunctiva/sclera to retina can be obtained by formulating
lipophilic drugs as hydrophilic drug/cyclodextrin complex
solutions,” write T. Loftsson and colleagues, University of
Iceland, Faculty of Pharmacy.
The researchers conclude, “Optimization of the delivery system
by formulating the drug as a low-viscosity aqueous drug/
cyclodextrin complex suspension results in sustained high
concentrations of dissolved drug in the tear fluid which further
increases the targeted drug delivery to the posterior segment.”
Loftsson and colleagues published their study in Pharmazie
(Topical Drug Delivery to the Posterior Segment of the Eye:
Anatomical and Physiological Considerations. Pharmazie,
2008;63(3):171-179).
Cambridge Consultants Offers Fast Track to Phase I
Clinical Trials for Inhalable Drugs with Development
Support for Conix
Drug Week via NewsEdge (NewsRx.com): May 8, 2008 – Cambridge Consultants (www.cambridgeconsultants.com) demonstrated a series of technology developments and services for its
Conix inhalable drug delivery technology at the Respiratory Drug
Delivery Conference in Scottsdale, AZ, for companies looking to
accelerate their move into Phase I clinical trials for their inhalable
drugs. Conix offers a low cost threshold previously not available
with traditional inhaler technology developments.
The company met with pharmaceutical and medical device
companies during the RDD Conference to demonstrate and
discuss a series of technology developments and support
services surrounding the Conix inhaler platform. The inhaler is
based around a novel “reverse flow cyclone” and contains no
moving parts or propellants. The inhaler can be made from a
single piece of plastic, where it would cost just 4¢ to
manufacture in high volume (5 million per annum). The unique
swirling action within the patented cyclone provides an
extremely effective de-agglomeration process, enabling a large
percentage of the drug to be delivered efficiently into the lung.
In-house tests with existing formulations from mass market
asthma and COPD inhalers have shown that the drug separation
mechanism is so efficient that it is up to 40% more effective than
many inhalers on the market today.
PharmaDerm to Expand Product Offerings with Purchase
of Vectoris Pharma—Newly Acquired Technology Allows
for Oral Delivery of Insulin
Drug Week via NewsEdge (NewsRx.com): May 8, 2008 – ICBS
Limited (ICBS) (Pink Sheets:ICBT) – PharmaDerm, an
international pharmaceutical venture between ICBS, McCoy
Enterprises, and Connell Associates, has announced that they
have acquired Vectoris Pharma, a company that has developed
an oral insulin, Perosulin®. Perosulin® is a needle-free, noninhaled insulin delivery technology.
PharmaDerm will commercialize Vectoris Pharma Corporation’s
proprietary platform drug delivery technology for trans-mucosal
drug delivery. The technology involves the use of a suspension
of large macro-molecular drugs, such as insulin, to facilitate
systemic delivery via the buccal membrane. The oral mucosa
provides a convenient route for macro-molecular delivery of
active agents. “Looking ahead in the development of this
needle-free platform technology, we envision the immediate
development of buccal delivery of insulin followed by pain
products such as fentanyl,” states Joe Connell, COO of
PharmaDerm. “We will focus our efforts on equipping military
and emergency personnel with a convenient, accurate, multipledose and needle-free atropine.”
PharmaDerm will be focused on licensing, developing, and
commercializing of Perosulin®. PharmaDerm will work with the
U.S. Food and Drug Administration (FDA) and The Health
Protection Branch of Canada to gain regulatory approval of
Perosulin® for commercialization.
In the News continued on page 32
31
t"306/%5)&(-0#&t"306/%5)&(-0#&t"306/%5)&(-0#&t"306
In the News continued from page 31
Study Data from Johnson & Johnson Update
Understanding of Drug Delivery
Drug Week via NewsEdge (NewsRx.com): May 8, 2008 – Current study results from the report “Supersaturating Drug Delivery
Systems: Effect of Hydrophilic Cyclodextrins and Other Excipients on the Formation and Stabilization of Supersaturated Drug
Solutions” have been published. According to recent research
from Belgium, “Supersaturating drug delivery systems (SDDS)
utilize two important design elements in their preparation including converting the drug of interest into a high energy state or other rapidly dissolving form to facilitate the formation of supersaturated drug solutions and providing a means for stabilizing the
formed supersaturated solution such that significant drug absorption is possible from the gastrointestinal tract. This has been referred to as a ‘spring’ and ‘parachute’ approach.”
“The current effort is designed to assess materials which may
affect properties in SDDS. To this end, a series of excipients was
tested in a co-solvent/solvent quench method to assess their
ability to attain and maintain supersaturation for a group of 14
drug development candidates. The approach focused on
hydrophilic cyclodextrins including hydroxypropyl-betacyclodextrin (HPbetaCD) and sulfobutyl-beta-cyclodextrin
(SBEbetaCD). Various rheological polymers and surfactants
were also included in the study. Consistent with previous
investigations, the pharmaceutical polymers, as a class, had
minimal effects on the extent of supersaturation but tended to be
good stabilizers while the surfactants tended to provide for the
greatest degree of supersaturation but the formed systems were
poorly stable. This study found that hydrophilic cyclodextrins,
especially SBEbetaCD, gave superior results in terms of
attaining and maintaining supersaturation,” write M. E. Brewster
and colleagues, Johnson & Johnson.
The researchers conclude, “A knowledge of the behavior and
performance of excipients in this context can be useful in
designing solid oral dosage forms for difficult-to-formulate
drugs and drug candidates.” Brewster and colleagues published
their study in Pharmazie (Supersaturating drug delivery systems:
Effect of hydrophilic cyclodextrins and other excipients on the
formation and stabilization of supersaturated drug solutions.
Pharmazie, 2008;63(3):217-220).
Study Data from Y. Chen and Colleagues Update
Understanding of Drug Delivery
Drug Week via NewsEdge (NewsRx.com): May 1, 2008 –
According to recent research from Wuhan, People’s Republic of
China, “A new self-microemulsifying drug delivery system
(SMEDDS) has been developed to increase the solubility,
dissolution rate and oral bioavailability of vinpocetine (VIP), a
poor water-soluble drug. The formulations of VIP-SMEDDS
were optimized by solubility assay, compatibility tests, and
pseudo-ternary phase diagrams analysis.”
“The optimal ratio in the formulation of SMEDDS was found to
be Labrafac:oleic acid: Cremophor EL: Transcutol P=40: 10:40:
32
10 (w/w). The average particle diameter of VIP was less than 50
nm. In vitro dissolution study indicated that the dialysis method
in reverse was better than the ultrafiltration method and the
dialysis method in simulating the drug in vivo environment.
[Compared] with VIP crude drug power and commercial tablets,
(-)VIP-SMEDDS caused a 3.4- and 2.9-fold increase in the
percent of accumulated dissolution at 3 h. Further study on the
absorption property of VIP-SMEDDS employing in situ intestine
of rats demonstrated that VIP in SMEDDS could be well-absorbed in [the] general intestinal tract without specific absorption
sites. In addition, the developed SMEDDS formulations significantly improved the oral bioavailability of VIP in rats. Relative
bioavailability of (-)VIP-SMEDDS and (+)VIP-SMEDDS increased by 1.85- and 1.91-fold, respectively, in [relation to] VIP
crude powder suspension,” write Y. Chen and colleagues.
The researchers conclude, “The mechanisms of enhanced
bioavailability of VIP might contribute to the improved release,
enhanced lymphatic transport, and increased intestinal
permeability of the drug.” Chen and colleagues published their
study in the Biological & Pharmaceutical Bulletin (Biological &
Pharmaceutical Bulletin, 2008;31(1):118-125).
APRIL 2008
Aradigm Announces Data Show No Occurrence of
Primary Lung Cancer in Patients Treated with AERx®
Insulin Diabetes Management System (iDMS)
Business Wire via NewsEdge: April 30, 2008 – HAYWARD,
Calif. – Aradigm Corporation (OTCBB:ARDM) has announced
that review of the clinical data by Novo Nordisk, with whom the
company had a collaboration for inhaled insulin, revealed no
occurrence of primary lung cancer in patients inhaling insulin
using the AERx® insulin diabetes management system (iDMS).
AERx iDMS uses an aqueous formulation of insulin delivered
by a hand-held electronic inhaler. Review of the clinical trial
data for AERx iDMS revealed no cases of primary lung cancer
in either the 2,307 patients treated with AERx iDMS or the 1,218
patients treated with comparator treatments.
Additionally, no treatment-related histological changes were
seen in the lungs of rats following a 6-month exposure period or
in monkeys exposed for a 9-month period. Furthermore,
quantitative evaluation of proliferating cells in the lungs of the
animals in these studies revealed no difference in proliferation
between the treatment and control groups. Such cell proliferation
assays are used to assess the potential for abnormal cell growth,
which may be a precursor for lung cancer.
Based on analysis of market data from Business Insights and
Wolters Kluwer PHAST, Aradigm believes that the market for
inhaled treatments of chronic respiratory diseases is estimated at
approximately $20 billion and growing at over 10% per year.
“Treatments of respiratory diseases by inhalation have proven to
be valuable to millions of patients with asthma, chronic
obstructive pulmonary disease (COPD), and cystic fibrosis,”
states Igor Gonda, Ph.D., the company’s president and CEO.
“Aradigm remains strongly committed to development of a
6/%5)&(-0#&t"306/%5)&(-0#&t"306/%5)&(-0#&t"306/%5)
pipeline of inhalation therapies to help patients with severe
respiratory diseases.”
Novo Nordisk previously announced the termination of its Phase
3 clinical trials for fast-acting inhaled insulin delivered via
AERx iDMS. Novo Nordisk stated they were not terminating the
trials because of any safety concerns. The latest review by Novo
Nordisk was in response to an announcement made by Pfizer
Inc. on April 24, 2008, that it has updated the product labeling
for Exubera®, a diabetes treatment inhaler that delivers dry
powder formulations containing insulin as the active ingredient,
to include a warning about lung cancer cases observed in
patients who received Exubera® in its clinical program. Pfizer
reported that in the clinical trials, 6 of 4,740 patients using
Exubera® developed lung cancer compared with 1 of 4,292
patients in the control arm. The labeling update by Pfizer further
stated that all patients who developed lung cancer had a prior
history of cigarette smoking and that there were too few cases to
determine whether the development of lung cancer was related
to the use of Exubera®.
Lux Biosciences’ Presentations at ARVO Highlight Both
Topical and Polymer Delivery Technologies Targeting
Chronic Inflammatory Ocular Diseases
Business Wire via NewsEdge: April 28, 2008 – JERSEY CITY,
N.J. – Next generation polymer technologies for the controlled
delivery of drugs and tailor-made product concepts for topical
delivery to the eye offer major market opportunities for new and/
or improved treatments for a variety of chronic inflammatory
ocular conditions, states Lux Biosciences, Inc., a privately held
biotechnology company specializing in the field of ophthalmic
diseases. Company scientists and collaborators presented data on
a proprietary topical product and new bioerodible polymer/drug
approaches for the treatment of dry eye and other inflammatory
eye diseases at the 2008 Annual Meeting of the Association for
Research in Vision and Ophthalmology (ARVO), in Fort
Lauderdale, FL.
“Some 15 - 20 million people in North America and Europe are
affected by chronic inflammatory diseases of the eye, which
include such conditions as dry eye, keratoconjunctivitis,
blepharitis and uveitis,” states Ulrich Grau, Ph.D., Lux
Biosciences president and chief executive officer. “Lux has
licensed Isotechnika, Inc.’s next generation calcineurin inhibitor,
voclosporin, for ophthalmic indications - the oral form of which
(LX211) is currently in phase 3 clinical development in uveitis.
By combining this molecule with innovative delivery
technologies, such as mixed micelles or bioerodible polymers,
we can deliver therapeutic concentrations of drug directly to the
eye in a targeted and sustained fashion, offering the potential to
greatly improve treatment for these widespread ocular
conditions.”
Prof. Ashim Mitra and colleagues from the University of
Missouri, Kansas City, in collaboration with Lux Biosciences,
presented a poster on the development of a clear, mixed micellar
formulation product (LX214) for the treatment of dry eye
syndrome and other potentially relevant ocular diseases.
Prof. Joachim Kohn and colleagues from the New Jersey Center
for Biomaterials of Rutgers, The State University of New Jersey,
and Lux Biosciences also gave an oral presentation on the
development of a bioerodible insert for ocular delivery of
voclosporin. The inserts under investigation were created from
polymers selected from a large combinatorial library of
bioerodible polyarylates and polycarbonates developed by the
Rutgers University researchers and licensed to Lux Biosciences
for ophthalmic use. When formulated with a drug, inserts
employing these polymers exhibit a new hybrid mechanism of
drug release that is capable of sustained drug delivery from 6 to
24 months. As such, these drug/polymer combinations have
potential clinical implications for the treatment of a variety of
immune-mediated ophthalmic conditions. The prototype
implants are very small, owing to the fact that the active
ingredient is very potent. More information can be found on the
company’s website at www.luxbio.com.
Studies from S. K. Jain and Co-researchers in the Area of
Diabetes Published
Diabetes Week via NewsEdge (NewsRx.com): April 24, 2008 –
According to recent research from Sagar, India, “In spite of
encouraging results of alternative parenteral dosage forms, the
problems of type I diabetes and insulin delivery remain a
challenging area of research. Glucose responsive liposomes
(GR) containing encapsulated insulin and GOD were prepared
using defined molar ratios of DPPE Egg PC, cholesterol and any
of three different fatty acids viz. oleic acid (GR-O1 & GR-O2),
palmitic acid (GR-P1 & GR-P2), stearic acid (GR-S1 &
GR-S2).”
“The control formulations include a non-glucose responsive
liposome (PS-L; no GOD) and non-pH-sensitive liposome
(NP-L; no pH-sensitive component). The GR formulations
showed a marked aggregation at pH 6.8-6.4 and a glucose
concentration dependent permeation and destabilization. In vitro,
insulin release was 21-31% within 0.5 h at 100 mg/dL glucose
incubation and was doubled (52-62%) at 250 mg/dL; the release
was slightly higher with the formulations of 2 molar ratios of
fatty acids. Following s.c. injection, the GR formulation showed
higher responses to reduce blood glucose (percentage of initial is
expressed) and were found to be 40-50% compared to control
formulations (PS-L; 61% and NP-L; 67 +/- 5.5%),” write S. K.
Jain and colleagues.
The researchers conclude, “Nonetheless, tailoring of controlled
release and long circulating forms of this carrier system may
improve its potential.” Jain and colleagues published their study
in the Journal of Drug Delivery Science and Technology (Journal
of Drug Delivery Science and Technology, 2007;17(6):399-405).
In the News continued on page 34
33
t"306/%5)&(-0#&t"306/%5)&(-0#&t"306/%5)&(-0#&t"306
In the News continued from page 33
New Drug Development Data Have Been Reported by
J. Woo and Co-authors
Cancer Weekly via NewsEdge (NewsRx.com): April 24, 2008 –
“A conventional, cholesterol-containing liposome formulation of
cisplatin has demonstrated insignificant activity in clinical trials,
due in part, to insufficient release of encapsulated content
following localization within solid tumors. For this reason, the
development of a triggered release liposome formulation is
desirable,” scientists in Vancouver, Canada, have reported.
“In this report, cisplatin was encapsulated into lysolipid-containing thermosensitive liposomes (LTSL) using a novel technique,
which relies on the equilibration of cisplatin across the liposomal
membrane at temperatures above the gel-to-liquid crystalline
phase transition temperature (T-C) of the bulk phospholipid. Mild
heating and drug loading into LTSL did not induce morphological
changes of the liposomes. In vitro data demonstrated that >95%
of encapsulated cisplatin was released from LTSL within 5 min
following mild heating at 42 degrees C, while <5% was released
at 37 degrees C. Under similar conditions, lysolipid-free thermosensitive liposomes exhibited 70% release of cisplatin at 42 degrees C, and cholesterol-containing liposomes exhibited negligible drug release at 42 degrees C. The pharmacokinetic profiles
of LTSL- and TSL-cisplatin indicated that these formulations
were rapidly eliminated from circulation (terminal t(1/2) of 1.09
and 2.83 h, respectively),” write J. Woo and colleagues.
The researchers conclude, “The therapeutic utility of LTSL-cisplatin formulation will be based on strategies where hyperthermia
is applied prior to the administration of the liposomal drug - a
strategy similar to that used in the clinical assessment of LTSLdoxorubicin formulation.” Woo and colleagues published their
study in the International Journal of Pharmaceutics (International Journal of Pharmaceutics, 2008;349(1-2):38-46).
Celator® Pharmaceuticals Successfully Uses Nanoparticles
to Administer Hydrophobic Drug Combinations
Cancer Weekly via NewsEdge (NewsRx.com): April 24, 2008 –
Celator Pharmaceuticals has reported results on a novel approach
designed to deliver drugs that are incapable of dissolving in water
(hydrophobic drugs) in nanoparticles to enhance and control drug
circulation. These findings allow the company to combine
hydrophobic drugs such as paclitaxel with other anti-cancer
drugs, based on the company’s proprietary CombiPlex
technology™. The results were presented in a poster presentation
at the American Association for Cancer Research meeting in
San Diego.
CombiPlex technology™ is a drug ratio technology platform that
represents a new approach that identifies a ratio of drugs that
will deliver a synergistic benefit, locks the desired ratio in a drug
delivery vehicle, and maintains the ratio in patients, with the
goal of improving clinical outcomes.
To date, Celator has utilized liposomes to deliver synergistic
drug combinations to treat cancer. Hydrophobic drugs such as
paclitaxel are not amenable to this form of delivery because they
34
detach from liposomes almost immediately after injection.
Celator scientists report that they were able to generate a library
of hydrophobic paclitaxel conjugates incorporated into
nanoparticles. In preclinical testing, these nanoparticles were
shown to circulate in the blood for more than 24 hr, allowing the
drug to accumulate selectively in solid tumors where it can then
be released and exposed to tumor cells.
According to the research findings, the ability to optimize
paclitaxel conjugates could make it possible for higher drug
levels to be maintained in plasma for extended periods, which is
associated with superior preclinical antitumor efficacy when
compared with drug delivery involving paclitaxel at its
maximum tolerated dose. In addition, preclinical studies
involving a drug conjugate of paclitaxel and gemcitabine coformulated into nanoparticles showed that a synergistic ratio of
the two drugs circulating in plasma was maintained for more
than 24 hr after intravenous injection.
Echo Therapeutics and Cato BioVentures Sign Right of
First Offer Agreement for Dermatology Products and
Transdermal Drug Delivery Technologies
Canada Newswire English via NewsEdge: April 21, 2008 –
FRANKLIN, Mass. – Echo Therapeutics (OTC Bulletin
Board:ECTE) has announced that it has signed a dermatology
product and transdermal drug delivery technology right of first
offer agreement with Cato BioVentures, the venture capital
affiliate of Cato Research, a global contract research and
development organization. The agreement grants Echo exclusive
rights of first negotiation to all dermatology product and
transdermal drug delivery technology opportunities identified or
acquired by Cato BioVentures.
“This agreement expands our long-standing strategic relationship
with Cato BioVentures and Cato Research and enables us to
leverage their deep industry access to a wide range of business
development opportunities in our core focus areas,” states
Patrick Mooney, M.D., Echo’s chair and CEO. “Cato is familiar
with our core transdermal platforms–AzoneTS™ for drug
reformulation and the Symphony tCGM System for non-invasive
continuous glucose monitoring–and understands our model to
leverage those platforms internally and with product and
technology acquisition opportunities that fit our model.”
Zelos Therapeutics and Aegis Therapeutics Announce
Collaboration for Intranasal Delivery of Zelos’ ZT-031
Business Wire via NewsEdge Corporation: April 16, 2008 –
WEST CONSHOHOCKEN, Pa., and SAN DIEGO, Calif. –
Zelos Therapeutics, Inc. and Aegis Therapeutics LLC have
announced the signing of a collaboration agreement for the
development of an intranasal spray formulation of the
proprietary parathyroid hormone (PTH) analog ZT-031
(Ostabolin-C™, cyclic PTH-(1-31)). Under the collaboration,
which is exclusive across the PTH field, Zelos will utilize Aegis’
patented Intravail® permeation enhancer technology to develop
an intranasal version of ZT-031 for the treatment of osteoporosis
and other bone diseases. A subcutaneous formulation of ZT-031
has already successfully completed a 12-month Phase 2 clinical
trial in the treatment of osteoporosis.
6/%5)&(-0#&t"306/%5)&(-0#&t"306/%5)&(-0#&t"306/%5)
EyeGate Pharma Initiates Phase I Study of EyeGate® II
Delivery System
Market Wire via NewsEdge Corporation: April 14, 2008 –
WALTHAM, Mass. – EyeGate Pharma, a privately held,
specialty pharmaceutical company using iontophoresis
technology to safely and non-invasively deliver therapeutics into
the front and back of the eye for treating serious ocular diseases,
has announced the initiation of a Phase I clinical study designed
to assess the safety and tolerability of the non-invasive
EyeGate® II ocular drug delivery system in up to 95 healthy
adult volunteers. This is a single-center, randomized, singlemasked, comparative-group safety and tolerability study of a
range of single iontophoretic dose levels with a citrate buffer via
the EyeGate®® II delivery system. For more information, visit
www.eyegatepharma.com.
MannKind Stumbles in Fallout From Exubera
in-pharmatechnologist.com: April 14, 2008 – MannKind has
suspended its search for a potential partner for its inhaled insulin
product Technosphere in the wake of the news of Exubera’s
possible cancer risk. The company still believes its treatment has
potential but given the current cynicism over the inhaled insulin
market has decided not to search for a partner at this time.
In its statement MannKind states, “At this time, we believe that
we will be unable to achieve an appropriate valuation for Technosphere Insulin until Phase III data are available that confirm our
belief in the safety and efficacy of Technosphere Insulin.”
MannKind is relying on good Phase III data for their inhaled
insulin treatment to reassure investors, the pharmaceutical
community, and the public of the safety of their product. The
trial is due to finish later this year, but the concern is that the
credibility of inhaled insulin is damaged beyond repair.
Many financial analysts have already written off the inhaled
insulin market following the news about Exubera. However,
MannKind believes its Technosphere Insulin has been more
thoroughly tested than Exubera, with a two-year carcinogenicity
study in rats showing that the product was well tolerated after
daily inhalations for 104 consecutive weeks.
Iomai and Merck & Co., Inc. Evaluate Use of Iomai
Immunostimulant Patch
Vaccine Weekly via NewsEdge Corporation (NewsRx.com):
April 10, 2008 – Iomai Corporation (NASDAQ:IOMI) has
announced that it has signed an agreement with Merck & Co.,
Inc. to conduct proof-of-principle preclinical studies evaluating
the use of the Iomai needle-free immunostimulant patch.
Merck has first option to negotiate an exclusive license. These
preclinical proof-of-principle studies will be conducted using an
undisclosed Merck vaccine. Iomai recently announced results of
a 500-person Phase 1/2 trial in which a clinically relevant
adjuvant effect was observed when a version of the
immunostimulant patch was administered in combination with
an injected vaccine for pandemic influenza, and data from a
prior European trial demonstrated the ability of the
immunostimulant patch to boost the immune response of the
elderly who receive an injected seasonal influenza vaccine.
The Iomai approach uses a potent adjuvant applied to the skin
through a patch that is affixed over the site of the injected
vaccine. Once the patch is applied, the adjuvant passes into the
skin, targeting cells called Langerhans cells. These specialized
skin cells carry the adjuvant into the lymph nodes, where it
works to boost an individual’s immune response to the vaccine.
This proprietary approach is known as transcutaneous
immunization (TCI).
Last year, the Department of Health and Human Services
(DHHS) awarded Iomai a $128 million contract to fund the
company’s development of a dose-sparing patch for use with a
pandemic influenza vaccine, and that contract is currently
funding the Phase 1/2 pandemic influenza trial. The patch being
used in that program is similar to the one that will be used in the
Merck collaboration, with the same adjuvant and delivery
system.
Research from Center for Drug Evaluation and Research
Yields New Findings
Drug Week via NewsEdge Corporation (NewsRx.com): April 10,
2008 – Research findings, “Lipid Excipients and Delivery
Systems for Pharmaceutical Development: A Regulatory
Perspective,” are discussed in a new report. “The use of lipidbased dosage forms for enhancement of drug absorption or
delivery has drawn considerable interest from pharmaceutical
scientists. The unique characteristics of these dosage forms,
however, present significant challenges to pharmaceutical
industry and regulatory agencies in many ways,” researchers in
the United States report.
“For example, safety assessment is necessary when the use of a
new lipid excipient is considered. An important question for lipid
formulation is whether the drug remains in solubilized form
along the gastrointestinal (GI) tract after it is administered.
Certain lipid excipients and surfactants have been reported to
change intestinal permeability or interfere with enzyme/
transporter activity, thereby affecting drug bioavailability. The
potential influence of biopharmaceutical and/or
pathophysiological factors on the drug or lipid excipient(s) needs
to be explored. For a complex lipid-based dosage form, the
conventional in vitro dissolution methods may not be appropriate
for predicting in vivo performance in view of the convoluted GI
processing of the lipid vehicle and formulation. Of paramount
importance is to identify any gaps in the scientific understanding
of lipid-based dosage forms so that regulatory issues can be
addressed. More mechanistic studies should be encouraged to
facilitate a better understanding of the pharmaceutical
characteristics of lipid formulations and complex interactions
between lipid excipient, drug and physiological environment.
This review discusses some regulatory considerations in the use
of lipid excipients and delivery systems for pharmaceutical
In the News continued on page 36
35
t"306/%5)&(-0#&t"306/%5)&(-0#&t"306/%5)&(-0#&t"306
In the News continued from page 35
development,” write M. L. Chen and colleagues, Center for Drug
Evaluation and Research.
The researchers conclude, “Implications in the regulatory
determination of pharmaceutical equivalence, bioequivalence
and therapeutic equivalence are also illustrated.” Chen and
colleagues published their study in Advanced Drug Delivery
Reviews (Lipid Excipients and Delivery Systems for
Pharmaceutical Development: A Regulatory Perspective.
Advanced Drug Delivery Reviews, 2008;60(6):768-777).
Study Results from Tabriz University of Medical Sciences,
Drug Applied Research Center
Drug Week via NewsEdge Corporation (NewsRx.com): April 10,
2008 – Scientists discuss new findings in life sciences in
“Swellable Elementary Osmotic Pump (SEOP): An Effective
Device for Delivery of Poorly Water-Soluble Drugs.” “A new
type of elementary osmotic pump (EOP) tablet for efficient
delivery of poorly water-soluble/practically insoluble drugs has
been designed. Drug release from the system, called swellable
elementary osmotic pump (SEOP), is through a delivery orifice
in the form of a very fine dispersion ready for dissolution and
absorption,” scientists writing in the European Journal of
Pharmaceutics and Biopharmaceutics report.
“SEOP tablets were prepared by compressing the mixture of
micronized drug and excipients into convex tablets. Factors
affecting the release of drug from the SEOP tablets containing a
poorly water-soluble drug, indomethacin, have been explored.
The release behaviour of indomethacin from different
formulations of this dosage form was studied at pH 6.8 for a
period of 24h. The formulations were compared based on four
comparative parameters, namely, D(24h) (total release after
24h), t(L) (lag time), RSQ(zero) (R square of zero order
equation) and D%(zero) (percentage deviation from zero order
kinetics). The drug release profile from osmotic devices showed
that the type of polymer in the core formulation can markedly
affect the drug release. The results showed that concentration of
wetting agent in the core formulation was a very important
parameter in D(24h) and release pattern of indomethacin from
SEOP system. Increasing the amount of wetting agent to an
optimum level (60mg) significantly increased D(24h) and
improved zero order release pattern of indomethacin. Increasing
concentration of caster oil (hydrophobic) in the semipermeable
membrane of the device or hydrophilic plasticizer (glycerin) in
coating formulation markedly increased t(L) and decreased
D(24h). The results also demonstrated that aperture size is a
critical parameter and should be optimized for each SEOP
system. Optimum aperture diameter for the formulations studied
here was determined to be 650microm for zero order release
pattern. t(L) and D%(zero) were dramatically decreased whereas
D(24h) and RSQ(zero) increased with increasing the aperture
size to optimum level,” write J. Shokri and colleagues, Tabriz
University of Medical Sciences, Drug Applied Research Center.
The researchers conclude, “This study also revealed that
optimization of semipermeable membrane thickness is very
important for approaching zero order kinetics.” Shokri and
36
colleagues published their study in the European Journal of
Pharmaceutics and Biopharmaceutics (Swellable Elementary
Osmotic Pump (SEOP): An Effective Device for Delivery of
Poorly Water-Soluble Drugs. European Journal of Pharmaceutics
and Biopharmaceutics, 2008;68(2):289-297).
Investigators at Pharmaceutical Research Center Zero in
on Life Sciences
Drug Week via NewsEdge Corporation (NewsRx.com): April 10,
2008 – Current study results from the report “Reduced FoodEffect and Enhanced Bioavailability of a Self-Microemulsifying
Formulation of Itraconazole in Healthy Volunteers” have been
published. “Self-microemulsifying drug delivery systems
(SMEDDS) represent a possible alternative to traditional oral
formulations of lipophilic compounds. This study was designed
to compare the oral bioavailability and food-effect of SMEDDS
of itraconazole (ITRA-GSMP capsule containing 50mg
itraconazole) to that of the currently marketed formulation
(Sporanox capsule containing 100mg itraconazole),”
investigators in Korea report.
“Eight healthy volunteers received Sporanox or ITRA-GSMP
capsule in the fasted state or after a high-fat diet on four separate
dosing occasions with a 2-week washout period. Blood samples
were collected and analyzed. After administration of the ITRAGSMP capsule, AUC0-24 and Cmax were 1.9- and 2.5-fold
higher in the fasted state and 1.5- and 1.3-fold higher in the fed
state, respectively, than those of the Sporanox capsule.
Moreover, ITRA-GSMP capsules yielded more reproducible
blood-time profiles than Sporanox capsules. Food had a marked
effect on itraconazole absorption from the Sporanox capsule,
whereas the influence was less pronounced for the ITRA-GSMP
capsule,” write J. S. Woo and colleagues, Pharmaceutical
Research Center.
The researchers conclude, “Collectively, our data suggest that a
new self-microemulsifying formulation may provide an
alternative oral formulation for itraconazole with improved oral
bioavailability and reduced food-effect.” Woo and colleagues
published their study in the European Journal of Pharmaceutical
Sciences (Reduced Food-Effect and Enhanced Bioavailability of
a Self-Microemulsifying Formulation of Itraconazole in Healthy
Volunteers. European Journal of Pharmaceutical Sciences,
2008;33(2):159-165).
Drug Delivery Study Findings from P. P. Constantinides
and Colleagues
Drug Week via NewsEdge Corporation (NewsRx.com): April 10,
2008 – Researchers detail new data in drug delivery in
“Advances in Lipid Nanodispersions for Parenteral Drug
Delivery and Targeting.” According to a study from the United
States, “Parenteral formulations, particularly intravascular ones,
offer a unique opportunity for direct access to the bloodstream
and rapid onset of drug action as well as targeting to specific
organ and tissue sites. Triglyceride emulsions, liposomes and
micellar solutions have been traditionally used to accomplish
these tasks and there are several products on the market using
these lipid formulations.”
6/%5)&(-0#&t"306/%5)&(-0#&t"306/%5)&(-0#&t"306/%5)
“The broader application of these lipid systems in parenteral
drug delivery, however, particularly with new chemical entities,
has been limited due primarily to the following reasons: a) only
a small number of parenteral lipid excipients are approved, b)
there is [an] increasing number of drugs that are partially or not
soluble in conventional oils and other lipid solvents, and c) the
ongoing requirement for site-specific targeting and controlled
drug release. Thus, there is [a] growing need to expand the array
of targetable lipid-based systems to deliver a wide variety of
drugs and produce stable formulations which can be easily
manufactured in a sterile form, are cost-effective and at least as
safe and efficacious as the earlier developed systems. These
advanced parenteral lipid-based systems are at various stages of
preclinical and clinical development which include
nanoemulsions, nanosuspensions and polymeric phospholipid
micelles.”
“This review article showcases these parenteral lipid
nanosystems and discusses advances in relation to formulation
development, processing and manufacturing, and stability
assessment. Factors controlling drug encapsulation and release
and in vivo biodistribution are emphasized along with in vitro/in
vivo toxicity and efficacy case studies. Emerging lipid excipients
and increasing applications of injectable lipid nanocarriers in
cancer chemotherapy and other disease indications are
highlighted and in vitro/in vivo case studies are presented,” write
P. P. Constantinides and colleagues.
The researchers conclude, “As these new parenteral lipid
systems advance through the clinic and product launch, their
therapeutic utility and value will certainly expand.”
Constantinides and colleagues published the results of their
research in Advanced Drug Delivery Reviews (Advances in Lipid
Nanodispersions for Parenteral Drug Delivery and Targeting.
Advanced Drug Delivery Reviews, 2008;60(6):757-767).
Monash University, Victorian College of Pharmacy,
Publishes Research
Drug Week via NewsEdge Corporation (NewsRx.com): April 10,
2008 – New investigation results are detailed in a study,
“Enhancing Intestinal Drug Solubilisation Using Lipid-Based
Delivery Systems,” published in Advanced Drug Delivery
Reviews. According to recent research from Parkville, Australia,
“Lipid-based delivery systems are finding increasing application
in the oral delivery of poorly water-soluble, lipophilic drugs.
Whilst lipidic dose forms may improve oral bioavailability via
several mechanisms, enhancement of gastrointestinal
solubilisation remains argueably the most important method of
absorption enhancement.”
“This review firstly describes the mechanistic rationale which
underpins the use of lipid-based delivery systems to enhance
drug solubilisation and briefly reviews the available literature
describing increases in oral bioavailability after the
administration of lipid solution, suspension and self-emulsifying
formulations. The use of in vitro methods including dispersion
tests and more complex models of in vitro lipolysis as indicators
of potential in vivo performance are subsequently described,
with particular focus on recent data which suggests that the
digestion of surfactants present in lipid-based formulations may
impact on formulation performance,” write C. J. Porter and
colleagues, Monash University, Victorian College of Pharmacy.
The researchers conclude, “Finally, a series of seven guiding
principles for formulation design of lipid-based delivery systems
are suggested based on an analysis of recent data generated in
our laboratories and elsewhere.” Porter and colleagues published
their study in Advanced Drug Delivery Reviews (Enhancing
Intestinal Drug Solubilisation Using Lipid-Based Delivery
Systems. Advanced Drug Delivery Reviews,
2008;60(6):673-691).
Study Findings Reported by Researchers at Novartis
Biotech Week via NewsEdge Corporation (NewsRx.com): April
10, 2008 – Research findings are discussed in a new report, “The
Potency of the Adjuvant, CpG Oligos, Is Enhanced by
Encapsulation in PLG Microparticles.” According to a study
from the United States, “The objective of this work was to
evaluate the potency of the CpG containing oligonucleotide
encapsulated within poly(lactide-co-glycolide), and
coadministered with antigen adsorbed to poly(lactide-coglycolide) microparticles (PLG particles). The formulations
evaluated include, CpG added in soluble form, CpG adsorbed,
and CpG encapsulated.”
“The antigen from Neisseria meningitidis serotype B (Men B)
was used in these studies. The immunogenicity of these
formulations was evaluated in mice. Poly(lactide-co-glycolide)
microparticles were synthesized by a w/o/w emulsification
method in the presence of a charged surfactant for the
formulations. Neisseria meningitidis B protein was adsorbed to
the PLG microparticles, with binding efficiency and initial
release measured. CpG was either added in the soluble or
adsorbed or encapsulated form based on the type of formulation.
The binding efficiency, loading, integrity and initial release of
CpG and the antigen were measured from all the formulations.
The formulations were then tested in mice for their ability to
elicit antibodies, bactericidal activity and T cell responses,” write
P. Malyala and colleagues, Novartis.
The researchers conclude, “Encapsulating CpG within PLG
microparticles induced statistically significant higher antibody,
bactericidal activity and T cell responses when compared to the
traditional method of delivering CpG in the soluble form.”
Malyala and colleagues published their study in the Journal of
Pharmaceutical Sciences (The Potency of the Adjuvant, CpG
Oligos, Is Enhanced by Encapsulation in PLG Microparticles.
Journal of Pharmaceutical Sciences, 2008;97(3):1155-1164).
Report by L. Chen and Co-researchers Describes Recent
Advances in Controlled Release
Biotech Week via NewsEdge Corporation (NewsRx.com): April
10, 2008 – According to recent research from Changchun,
People’s Republic of China, “This paper presented a new
In the News continued on page 38
37
t"306/%5)&(-0#&t"306/%5)&(-0#&t"306/%5)&(-0#&t"306
In the News continued from page 37
approach for preparing a new type of slow-release membraneencapsulated urea fertilizer with starch-g-PLLA as
biodegradable carrier materials.”
“By solution-casting and washing rapidly with water the urea
was individually encapsulated within the starch matrix modified
by L-lactide through in situ graft-copolymerization. The release
behavior of urea encapsulated in the films was studied, and [the]
following conclusions were achieved: (1) the introduction of
hydrophobic PLLA reduced the swellability of [the] starch
matrix and decreased the release rate of urea; (2) the urea release
rate could be controlled from several hours to 1 day by adjusting
the graft efficiency; (3) scanning electron microscopy revealed
that the urea encapsulated within the starch matrix was
uniformly dispersed in the form of tiny cell and the urea
encapsulated in the modified starch film released through a
diffusion mechanism,” write L. Chen and colleagues.
The researchers conclude, “Therefore, the modified starch
products for controlled release could be expected to have widely
potential application in agriculture industry as fertilizer carrier.”
Chen and colleagues published their study in Carbohydrate
Polymers (Carbohydrate Polymers, 2008;72(2):342-348).
Researchers at Zhejiang University, College of
Pharmaceutical Sciences, Release New Data
Drug Week via NewsEdge Corporation (NewsRx.com): April
10, 2008 – New investigation results are detailed in a study,
“Solubility-Modulated Monolithic Osmotic Pump Tablet for
Atenolol Delivery,” published in the European Journal of
Pharmaceutics and Biopharmaceutics. “A method for the
preparation of monolithic osmotic pump tablet was obtained by
modulating atenolol solubility with acid. Tartaric acid was used
as solubility promoter, sodium chloride as osmotic agent and
polyvinyl pyrrolidone as retardant agent,” investigators in
Hangzhou, People’s Republic of China, report.
“Ethyl cellulose was employed as semipermeable membrane
containing polyethylene glycol 400 as plasticizer. The
formulation of atenolol monolithic osmotic pump tablet was
optimized by orthogonal design and evaluated by similarity
factor (f(2)). The optimal monolithic osmotic pump tablet was
found to be able to deliver atenolol at the rate of approximate
zero-order up to 24h, independent of release media and agitation
rate,” write L. Liu and colleagues, Zhejiang University, College
of Pharmaceutical Sciences.
The researchers conclude, “The approach of solubilitymodulated by acid-alkali reaction might be used for the
preparation of osmotic pump tablet of other poorly water-soluble
drugs with alkaline or acid groups.” Liu and colleagues
published their study in the European Journal of Pharmaceutics
and Biopharmaceutics (Solubility-Modulated Monolithic
Osmotic Pump Tablet for ateNolol Delivery. European Journal
of Pharmaceutics and Biopharmaceutics, 2008;68(2):298-302).
38
New Biopharmaceuticals Research Reported by Scientists
at University College
Drug Week via NewsEdge Corporation (NewsRx.com): April 10,
2008 – Scientists discuss new findings in biopharmaceuticals in
“Biopharmaceutical Challenges Associated with Drugs with Low
Aqueous Solubility—The Potential Impact of Lipid-Based
Formulations.” “The percentage of new chemical entities
synthesized with low aqueous solubility and high therapeutic
efficacy is growing, this presents major challenges for the drug
delivery scientists. The role of physicochemical properties in
identification of suitable drug candidates for oral lipid-based
delivery systems is discussed,” investigators in Cork, Ireland,
report.
“A knowledge of the interplay of physicochemical and
biopharmaceutical drug properties with the physiological
environment of the gastro-intestinal tract (GIT), as a prerequisite
to successful formulation design, is reviewed. The importance of
excipient selection with an emphasis on bioactive excipients is
stressed,” write C. M. O’Driscoll and colleagues, University
College.
The researchers conclude, “The need for more examples of in
vitro-in vivo correlations as a means of maximizing the
development potential and commercial future for lipid-based
formulations, and, promoting confidence within the industry for
these delivery systems is highlighted.” O’Driscoll and colleagues
published their study in Advanced Drug Delivery Reviews
(Biopharmaceutical Challenges Associated with Drugs with Low
Aqueous Solubility—The Potential Impact of Lipid-Based
Formulations. Advanced Drug Delivery Reviews,
2008;60(6):617-624).
Reports from Kyoto University Describe Recent Advances
in Solid Cancer Therapy
Cancer Weekly via NewsEdge Corporation (NewsRx.com):
April 10, 2008 – Data detailed in “Anti-tumor Effect of AllTrans Retinoic Acid Loaded Polymeric Micelles in Solid Tumor
Bearing Mice” have been presented. “All-trans retinoic acid
(ATRA) polymeric micelles were developed for parenteral
administration. The distribution characteristics and antitumor
activities of ATRA polymeric micelles were evaluated after
intravenous administration to mice bearing CT26 solid tumors,”
scientists in Kyoto, Japan, report.
“ATRA incorporated in poly(ethylene glycol)-poly(benzyl
aspartate) block copolymer was prepared by the evaporation
method. The levels of [3H]ATRA in blood and tissue including
tumor were determined by measuring the radioactivity after
injection into mice. The tumor volume and the survival of the
mice were determined to assess the anticancer activity. The
delivery of ATRA by polymeric micelles prolonged the blood
circulation and enhanced the accumulation of ATRA in the tumor
tissue compared with the administration of free ATRA. Tumor
growth was significantly delayed and the survival time of mice
was prolonged following the treatment by ATRA polymeric
6/%5)&(-0#&t"306/%5)&(-0#&t"306/%5)&(-0#&t"306/%5)
micelles demonstrating the improved anticancer activity of
ATRA,” write N. Chansri and colleagues, Kyoto University.
The researchers conclude, “Polymeric micelles are a promising
and effective carrier of ATRA in order to enhance tumor delivery
and they have a promising potential application in the treatment
of solid tumors.” Chansri and colleagues published their study in
Pharmaceutical Research (Anti-tumor Effect of All-Trans
Retinoic Acid Loaded Polymeric Micelles in Solid Tumor
Bearing Mice. Pharmaceutical Research, 2008; 25(2):428-434).
New Drug Delivery Research from Silpakorn University,
Department of Pharmaceutical Technology
Drug Week via NewsEdge Corporation (NewsRx.com): April 10,
2008 – Researchers detail new data in drug delivery in
“Development of Time-, pH-, and Enzyme-Controlled Colonic
Drug Delivery Using Spray-Dried Chitosan Acetate and
Hydroxypropyl Methylcellulose.” According to recent research
from Nakhon Pathom, Thailand, “A colonic drug delivery with a
new concept based on a combination of time-, pH-, and enzymecontrolled system was developed. Spray-dried chitosan acetate
(CSA) prepared from low molecular weight chitosan was
characterized.”
“A combination of CSA and hydroxypropyl methylcellulose
(HPMC) was used as new compression-coats for
5-aminosalicylic acid (5-ASA) tablets. Factors affecting in-vitro
drug release, i.e. % weight ratio of coating polymers, enzyme
activity, pH of media, and excipients in core tablets, were
evaluated. The tablets compression-coated with HPMC:CSA at
60:40 and 50:50% weight ratio providing lag times [of] about
5-6h were able to pass through the stomach (stage I, 0.1N HCl)
and small intestine (stage II, pH 6.8, Tris-HCl). The delayed
release was time-and pH-controlled owing to the swelling with
gradual dissolving of CSA and HPMC in 0.1N HCl and the less
solubility of CSA at higher pH. After reaching the colon (stage
III, pH 5.0, acetate buffer), the dissolution of CSA at low pH
triggered the drug release over 90% within 14h,” write J.
Nunthanid and colleagues, Silpakorn University, Department of
Pharmaceutical Technology.
The researchers conclude, “Furthermore, the degradation of CSA
by beta-glucosidase in the colonic fluid enhanced the drug
release while adding the disintegrant or the osmotic agent in the
core tablets would affect the drug release.” Nunthanid and
colleagues published their study in the European Journal of
Pharmaceutics and Biopharmaceutics (Development of Time-,
pH-, and Enzyme-Controlled Colonic Drug Delivery Using
Spray-Dried Chitosan Acetate and Hydroxypropyl
Methylcellulose. European Journal of Pharmaceutics and
Biopharmaceutics, 2008;68(2):253-259).
MARCH 2008
Acusphere Licenses Hydrophobic Drug Delivery System
to Cephalon for $10 Million
Business Wire: March 31, 2008 – WATERTOWN, Mass. –
Acusphere Inc. (NASDAQ: ACUS) has announced that it has
signed an agreement to license the intellectual property rights to
its Hydrophobic Drug Delivery System™ (HDDS) for oncology
applications, along with the rights to AI-850, its formulation of
paclitaxel, to Cephalon, Inc., in exchange for a cash payment of
$10 million.
“We are very pleased with the terms of this transaction, which
establishes a strong value for part of our technology platform
that is at an early stage of development,” states Sherri C. Oberg,
president and CEO of Acusphere. “We are confident that
Cephalon is the right partner for one application of this
important technology, given its strong focus on oncology. Just
six months ago, we announced that AI-850 was a potential bioequivalent to the one of the fast-growing anti-cancer drugs,
Abraxane®. This transaction confirms the potential for our
technology in the oncology arena, which is one of many
potential applications for our HDDS technology.”
Frank Baldino, Jr., chair and CEO of Cephalon, states,
“Cephalon has a growing oncology business with a deep and
diverse portfolio of marketed products and pipeline compounds.
The addition of the HDDS technology, and AI-850 in particular,
will build on our expertise and expand our oncology portfolio.”
Abuse-Resistant Oxycodone Primed for Clinical Trials
in-pharmatechnologist.com: March 30, 2008 –
IntelliPharmaCeutics is ready to move into full-scale clinical
trials with a once-daily oral formulation of oxycodone based on
the company’s ReXista abuse- and alcohol-resistant technology.
A drug delivery specialist based in Toronto, Canada,
IntelliPharmaCeutics has successfully completed a pilot clinical
study with its controlled-release version of oxycodone, the
notoriously abuse-prone opioid analgesic whose appeal to
addicts has earned it the monicker “hillbilly heroin.” The study
found that the ReXista formulation of oxycodone was
bioequivalent in a single dose to two doses of the reference drug,
Purdue Pharma’s Oxycontin.
IntelliPharmaCeutics’ ReXista formulation of oxycodone is
designed to resist abuse by oral ingestion when the drug is
crushed or chewed, by injection when it is combined with
solvents, or by nasal application when oxycodone is crushed or
powdered. It also guards against the entire daily dose of
oxycodone being released when the drug is taken with alcohol
“in any quantity,” IntelliPharmaCeutics notes. This problem is
“so serious with some opioid drugs, such as hydromorphone,
that their use has been limited or curtailed by the FDA,” the
company adds.
In the News continued on page 40
39
t"306/%5)&(-0#&t"306/%5)&(-0#&t"306/%5)&(-0#&t"306
In the News continued from page 39
The goal of the pilot clinical trial was to compare the
pharmacokinetics of ReXista oxycodone in a single 40-mg
dosage form with 20-mg of Oxycontin given twice daily under
fasted conditions. The outcome was that the ReXista product
demonstrated sustained-release pharmacokinetic activity, with
blood plasma concentrations at clinically significant levels over
a 24-hr period, IntelliPharmaCeutics reports. The company plans
to release detailed results of the pilot trial after further study and
analysis. “With these results in hand, we will certainly move
rapidly to advance the development into a full clinical trial
program,” comments Chief Executive Officer Dr. Isa Odidi.
Inhaled TB Vaccine Shows Promising Results
in-pharmatechnologist.com: March 20, 2008 – Animal studies
reveal that we may be on the road to creating the first inhaled
vaccine for tuberculosis, with results showing the vaccine to be
at least as effective as the injected form. The inhaled vaccine,
which takes the form of a fine powder, would be easier to
administer in third world countries, as it does not require
needles, syringes, or water, and it does not need to been
refrigerated during transport.
The vaccine, developed by researchers at Harvard University and
tested by scientists at the University of North Carolina at Chapel
Hill, is based on the Bacille Calmette-Guérin (BCG) vaccine
commonly used throughout the world, which takes the form of
weakened Mycobacterium bovis cells from the cow form of TB.
In the injectable form these cells are freeze dried, to preserve the
cells in a weakened but living state during storage and
transportation before use. However, vaccines prepared in this
way need to be refrigerated throughout transportation, and it
must be mixed with water to be able to administer the vaccine
through an injection, making it impractical to administer under
the conditions of the developing world.
An inhaled dry-powder vaccine would solve some of these
problems, as delivery through an inhaler is non-invasive and
does not require water. “The vaccine is stable and can be
transported and stored without refrigeration. In addition, the ease
associated with simply inhaling the vaccine makes it suitable for
delivery in any location without risk of contamination,” says
Tony Hickey, University of North Carolina. However, until now
it had been hard to create a powder with fine enough particles to
safely administer directly to the lungs. The team solved this by
using special additives and a spray-drying process, where the
cells are sprayed through heated gas to create a dry powder
before storage.
When tested on animals the results seem very promising, with
better results for the inhaled vaccine compared with the injected
vaccine. “After delivering the vaccine to the animals and then
exposing them to infectious micro-organisms only 1 per cent
survive in the lungs of animals immunised by the pulmonary
route while 5 per cent survive in those treated with the usual
injection,” states Hickey. However, he remains cautious as to
how these results will translate to humans.
40
U.S. Team Claims a First in Nanovalves for Drug Delivery
in-pharmatechnologist.com: March 19, 2008 – A team of
nanotechnologists and chemists based in the United States has
created a novel nanovalve that could be used to deliver
medications according to the pH environment in the body. The
approach is novel because the nanovalve is capable of
functioning in an aqueous environment under physiological
conditions, in contrast to older conformations that were only
stable while immersed in organic solvents. Eventually, the aim of
the project is to develop a structure that can pass into cells and
respond to the very small differences in pH that occur in
diseased and healthy tissues, allowing the release of
therapeutically active agents only in diseased cells.
Scientists at the University of California, Los Angeles,
NanoSystems Institute modified the surfaces of porous, dyefilled nanospheres, creating stem-like structures. On top of this
primary scaffolding, the team stacked a series of cucurbit[6]uril
units (molecular baskets formed from repeated glycouril that
have a characteristic “squashed pumpkin” formation), creating—
at neutral to acidic pH—a mechanically-interlocking
pseudorotaxane architecture that blocks the nanosphere pores,
thereby preventing the release of a test agent, a dye called
rhodamine, held within.
When the local pH is moved into the basic range, the
intramolecular bonds holding the structure in place are
weakened, causing the nanosphere pores to open and the dye to
be released, while maintaining the structures’ overall
2D-hexagonal formation. The team used luminescence
spectroscopy to measure the release of the dye, confirming via
absorption analysis that for every 15 mg of the particles an
average of 3 mmol of dye was released.
In effect, the researchers have created a supramolecular
conformation that acts as a controllable molecular valve that is
stable in an aqueous environment. The research team, under the
leadership of J. Fraser Stoddart and Jeffrey I. Zink, state that
although the aqueous-stable nanovalve represents a significant
breakthrough in nanomolecular architecture, further work needs
to be undertaken to fine tune the process. The technology is
described in a paper published in the German journal
Angewandte Chemie.
Lilly Declines to Inhale with AIR Insulin Program
in-pharmatechnologist.com: March 11, 2008 – The prospects for
a viable market in inhaled insulin therapies are looking markedly
thinner after Eli Lilly pulled the plug on its joint development
program with drug delivery specialist Alkermes for AIR Insulin.
Lilly is taking an estimated $90–120m charge ($0.05–0.07 per
share) to earnings in the first quarter to terminate development of
the inhaled insulin incorporating Alkermes’ proprietary AIR
pulmonary technology. The decision scraps a seven-year effort
that has seen Lilly recruit thousands of diabetes patients for
clinical trials. It comes only weeks after Novo Nordisk dropped
its own AERx inhaled insulin system from late development, at a
cost of DKK1.3bn ($0.267bn), having concluded the product
was unlikely to offer significant clinical or convenience benefits
over insulin injections with pen devices.
6/%5)&(-0#&t"306/%5)&(-0#&t"306/%5)&(-0#&t"306/%5)
In an earlier update on the AIR Insulin program, which
prefigured Lilly’s announcement by revealing that the company
was “evaluating its business case for AIR Insulin” and was
expected to “make a decision to discontinue the program in the
next week,” Alkermes indicated a willingness to continue with
the Phase III program regardless of Lilly’s commercial
intentions.
the tumor without needing to increase the actual dosage of the
drug. Ferrari is currently investigating the possibility of using the
particles to deliver short interfering RNA (siRNA) molecules
that could silence messenger RNA within a tumor cell to stop it
reproducing. Ferrari presented his research in the March issue of
Nature Biotechnology.
MicroDose and Merck Agree to $32M for DPI Deal
“While Lilly may elect not to commercialize AIR Insulin,
Alkermes believes that the Phase III safety and efficacy trials
should be completed,” it states. “Data from these studies will
provide patients, physicians and the scientific community with
long-awaited and important data for the evaluation of new
diabetes medications.” Whether Alkermes has the resources to
carry on development of AIR Insulin without an immediate
partner should emerge once the company has taken a closer look
at its options.
‘Nested’ Nanoparticles Increase Efficiency of Drug
Delivery
in-pharmatechnologist.com: March 6, 2008 – A “matryoshka
doll” filled with drugs could be the missing link that finally
allows nanomedicine to fulfill its potential. University of Texas
researchers believe that by encasing their drugs in a series of
nanoparticles they can produce a highly targeted treatment that
bypasses the body’s immune defenses, which have typically
plagued other nanotechnology therapies.
These defenses protect the body from foreign bodies that enter
the bloodstream, including therapeutic nanoparticles. The
different levels of attack include enzymes in the blood that
corrode the particles and microphage cells that actively attack
and destroy the particles and remove them from the bloodstream.
The drug must then penetrate the vessel walls to reach deep
inside the tumor. These defenses are so effective that on average
just one out of every 100,000 drug molecules actually end up in
the area they were meant to be targeting. In the past it has been
difficult to find particles that could both penetrate these
“biobarriers” and effectively find and target the correct tumor
cells.
Mauro Ferrari’s multistage delivery system overcomes these
defenses using a series of nanoparticles, contained one inside the
other. As it passes through each barrier the drug sheds a shell to
reveal a new particle that is best suited to the next line of
immune defense. “Silicon is fully biodegradable to a rate that
can be carefully controlled, and the degradation products are
harmless and produced in quantities much lower than the
average dietary intake. In addition, we know how to manufacture
its size, shape, and charge density to a great variability - as used
in the microelectronics industry,” explains Ferrari.
Once in their desired position, the silicon particles can release
quantum dots or carbon nanotubes—both of which act as
contrast agents for imaging applications. The carbon nanotubes
can also be stimulated to produce heat, which itself could be
used as a therapy. These particles can also be used to deliver
other therapeutic agents, to achieve high concentrations within
in-pharmatechnologist.com: March 5, 2008 – Merck & Co has
signed a $32m deal to evaluate MicroDose Technologies’ dry
powder inhalation technology in the delivery of some of its
respiratory product lines. MicroDose’s DPI system has already
attracted interest from several major pharmaceutical firms,
including Switzerland’s Novartis. It is a handheld, low-cost,
breath-activated device that utilizes piezo electronics to deliver
compounds and is suitable for both small or large molecule
therapeutics and for local and systemic applications.
The administration of pharmaceuticals through the respiratory
tract is one of the most established methods of drug delivery.
The large surface area and associated blood supply make the
lungs an ideal means of rapidly disseminating medications. At
present, conditions such as asthma and chronic obstructive
pulmonary disease are routinely treated using aerosolized
inhalable medications, as opposed to the many injectable
treatments that are also available.
Scott Fleming, senior vice president, marketing, of MicroDose,
states, “This agreement to bring innovative inhalation products
to market is a positive milestone in the continued growth of
MicroDose and represents further validation of our DPI
technology.” Soren BoChristiansen, general manager of Merck’s
bone, respiratory, immunology, and endocrinology franchises,
echoes these thoughts, commenting,” through this agreement
Merck has gained access to a novel delivery technology that has
the potential to facilitate the administration of and ensure patient
compliance with drug treatments targeting the lungs.”
FEBRUARY 2008
Novozymes and Upperton Move Nanoparticles Toward
Commercialization
in-pharmatechnologist.com: February 21, 2008 – Denmark’s
Novozymes has renewed and extended its collaboration with
U.K.-based biotech Upperton Limited on a drug delivery system
that exploits the natural binding properties of recombinant protein
nanoparticles to improve compound targeting and bioavailability.
The new agreement focuses on the commercial exploitation of the
companies’ jointly owned rP-nano technology, which Upperton
will use to generate nanoparticles from recombinant proteins
expressed in Novozymes’ proprietary yeast-based system.
The current focus is on drug and gene delivery, for example,
cancer therapeutics, vaccines, DNA/iRNA, pulmonary delivery
or localized delivery for wound-healing/topical applications. The
scope could also extent to in vitro diagnostics and personal care
products.
In the News continued on page 42
41
t"306/%5)&(-0#&t"306/%5)&(-0#&t"306/%5)&(-0#&t"306
In the News continued from page 41
U.K. Team to Use Nanoparticles to Improve Brain Drug
Delivery
in-pharmatechnologist.com: February 20, 2008 – A nanoparticlebased delivery system is being developed in the United
Kingdom as a potential means of bypassing the blood-brain
barrier and improve the treatment of central nervous system
diseases such as brain cancer. One example of such work is
research being conducted by scientists at the University of
Portsmouth, in the United Kingdom. The three-year project,
which is funded by a £451,000 ($880,000) grant from the
Biotechnology and Biological Sciences Research Council, is
using polymer-based nanoparticles to modify a naturally
occurring peptide capable of creating temporary openings in the
blood-brain barrier, allowing for improved drug delivery.
Project leader Dr. Eugen Barbu and colleagues will develop
particles of approximately one-thousandth the width of a single
human hair that are able to both breach the blood-brain barrier
and act as a delivery container for the medications. Dr. Barbu
explains that the team has chosen to work with natural polymers
due to their lack of toxicity and ability to biodegrade.
Prof. Darek Gorecki, who will be working alongside Dr. Barbu,
states, “the BBSRC thought it was worth investing half a million
pounds because though other scientists are studying ways of
penetrating the blood brain barrier, this idea of using modified
natural polymers is novel.” He cautions however that the work is
still at an experimental stage and is unlikely to have a direct
impact on drug delivery for some time. Prof. Gorecki adds, “we
are hoping that by using modified polymers working in various
ways we can generate a temporary opening in the cells of the
blood brain barrier and allow drugs to be delivered straight to
the brain.” The hope is that in the future such a nanoparticlebased delivery approach can improve the delivery of therapy for
a broad spectrum of brain disorders ranging from stroke to
Alzheimer’s.
Fentanyl Patches Recalled Over Leakage Risk
in-pharmatechnologist.com: February 20, 2008 – Concerns have
been building across North America about the safety of
transdermal patches for delivering the highly potent narcotic
analgesic fentanyl. Both brand-name and generic companies
selling fentanyl patches have recalled some of their products
voluntarily due to the risk of a potentially life-threatening
manufacturing defect.
The problems emerged when PriCara, a division of OrthoMcNeil-Janssen Pharmaceuticals, said all lots of 25 µg/hr
Duragesic (fentanyl transdermal system) CII patches sold by
PriCara in the United States, as well as all 25 µg/hr fentanyl
patches sold as an authorized generic by Sandoz in the same
market, were being recalled voluntarily “as a precaution” from
wholesalers and pharmacies. The action was taken in cooperation with the U.S. Food and Drug Administration (FDA).
The patches involved all had expiry dates of December 2009 or
earlier and were all manufactured by Alza, the drug delivery
42
specialist that, like PriCara, is part of the Johnson & Johnson
group.
All 25 µg/hr fentanyl patches manufactured by Alza and sold in
Canada—by both Janssen-Ortho as Duragesic and by Ranbaxy
as Ran fentanyl transdermal system patches, under an October
2006 licensing and supply agreement between Janssen-Ortho
and Ranbaxy Pharmaceuticals Canada—were also taken off the
market. The Canadian regulatory authority, Health Canada,
issued a public health advisory warning against use of the
affected patches. Another company that has taken precautionary
measures over potential defects in fentanyl patches is one of
PriCara’s generic competitors, Actavis.
The company has voluntarily recalled 14 lots of fentanyl
transdermal system CII patches sold in the United States by its
subsidiary Actavis South Atlantic LLC. The lots in question were
manufactured for Actavis on contract by Corium International.
The recalled lots “may have a fold-over defect which may cause
the patch to leak and expose patients or caregivers directly to the
fentanyl gel,” Actavis states, adding that it was “unaware of any
injuries resulting from this issue.”
Targeted Nanoparticles Open Up Cartilage to Drug
Delivery
in-pharmatechnologist.com: February 19, 2008 – A novel
delivery system that converts the structure of cartilage “from a
barrier into a reservoir” could provide an answer to the challenge
of administering and maintaining drugs in avascular tissue.
Modified polymeric nanoparticles developed by researchers at
the École Polytechnique Fédérale de Lausanne in Switzerland
and the University of Massachusetts in the United States were
found in animal studies to accumulate in an extracellular matrix
(ECM) of articular cartridge at concentrations of up to 72 times
more than non-targeted nanoparticles, remaining in the matrix
without statistically significant clearance for up to 96 hr.
As Jeffrey Hubbell et al. point out in a paper published in Nature
Materials, delivering drugs to cartilage for purposes such as
treating early degradation in osteoarthritis is usually hampered
by poor bioavailability due to the lack of vascularized tissue and
the dense ECM, which acts as a barrier to entry.
The avascularity of cartilage tissue favors regional
administration of the drug within the joint space rather than into
the systemic circulation. However, compounds are rapidly
cleared from the synovial fluid into the lymphatic system,
accounting for the low bioavailability and raising the possibility
of adverse systemic effects. The researchers sought to overcome
these obstacles by developing particles that would be small
enough to enter the cartilage matrix, as it is dynamically
compressed during normal movement, and would display
sufficient affinity for a cartilage ECM component to be retained
there. Targeting of the cartilage matrix “is likely to be an
important factor in future pharmaceutical approaches for the
treatment of osteoarthritis,” they suggest.
6/%5)&(-0#&t"306/%5)&(-0#&t"306/%5)&(-0#&t"306/%5)
West Pharmaceutical and Nektar Formally Sever Exubera
Ties
in-pharmatechnologist.com: February 19, 2008 – West
Pharmaceutical Services has formally announced the end of its
Exubera relationship with the product’s developers, Nektar
Therapeutics. The contract manufacturer, whose Tech Group
division was jointly responsible along with the United
Kingdom’s Consort Medical for manufacturing the inhaled
insulin device, says it will now be reimbursed for facility,
inventory, raw materials, and personnel costs “at levels that are
consistent with the company’s previously announced
expectations.”
In November, Nektar’s Exubera commercialization partner Pfizer
agreed to pay Nektar $135m in compensation for unexpectedly
pulling the Exubera device from the market due to poor sales. It
also agreed to hand over its commercial interest and regulatory
filings for the product. Nektar still has faith in the product’s
ability to sell and is seeking a new partner for the troubled
device.
The repercussions of Pfizer’s dramatic Exubera exit from the
market have been gradually filtering through to the West, with
the company preparing to restructure its affected Tech Group
contract manufacturing unit.
Anti-AIDS Gel Disappoints, Failing to Prevent HIV
Infection in Study of African Women
Associated Press WorldStream via NewsEdge Corporation:
February 18, 2008 – The first anti-AIDS vaginal gel to make it
through late-stage testing failed to stop HIV infection in a study
of 6,000 South African women, disappointed researchers have
announced. The study was marred by low use of the gel, which
could have undermined results, they state. Women used it less
than half the number of times they had sex, and only 10% said
they used it every time as directed.
Scientists are still analyzing the results to see if this made a
difference. They also plan more tests on a revamped gel
containing an AIDS drug that they hope will work better. The gel
used in the current study did prove to be safe, however, and
researchers called this a watershed event. But for now, the effort
is the latest disappointment in two decades of trying to develop a
microbicide—a cream or gel women could use to lower their risk
of getting HIV through sex. A female-controlled method is
especially needed in poor countries where women often can’t
persuade men to use condoms.
A year ago, scientists stopped two late-stage tests of a different
gel after early results suggested it might raise the risk of HIV
infection instead of lowering it. The new study tested
Carraguard, a microbicide developed by the nonprofit, New
York-based Population Council. It contains carrageenan, which
comes from seaweed and is widely used in the food and
cosmetics industries as a gel, stabilizer, and thickening agent.
Lab, animal, and early human tests suggested it might prevent
HIV and other sexually spread infections. The latest study was
done from March 2004 through March 2007 in Gugulethu,
Isipingo, and Soshanguve, all in South Africa.
The Population Council hopes to start tests this year of a
revamped Carraguard containing an experimental AIDS drug,
MIV-150. The group also has studies under way on a
contraceptive version of the gel, Carraguard plus hormones.
Study Results from J. J. Sun and Colleagues Broaden
Understanding of Drug Development
Drug Week via NewsEdge Corporation (NewsRx.com):
February 14, 2008 – “In recent years the interest of sustained
drug delivery into [the] inner ear [has been] promising, at the
same time a great deal of novel oral drugs using biodegradable
vehicles have been produced to achieve sustained drug release.
The aim of this study was to use biodegradable vehicles to
release dexamethasone in the round window membrane
application,” investigators in Beijing, People’s Republic of
China, report.
“Dexamethasone gels composed of alginate and chitin were
prepared and the release-permeating profiles were studied using
a reproducible in vitro apparatus. A longer-period time course
was simulated using the parameters acquired in this study. The
data obtained in this study was compared with those of other
studies in intratympanic drug delivery, and an appropriate initial
dosage was extrapolated. The combination of alginate and chitin
could efficiently restrict dexamethasone diffusion and the time
course suggested a sustained drug concentration within 24 hours.
A higher initial dosage was estimated to achieve a stable
therapeutic concentration in vivo,” write J. J. Sun and
colleagues.
The researchers conclude, “The combination of alginate and
chitin could be used as [a] vehicle for sustained release of
dexamethasone in intratympanic application.” Sun and
colleagues published their study in the Chinese Medical Journal
(Chinese Medical Journal, 2007;120(24):2284-2289).
Patch Instead of Pills Makes Living with Alzheimer’s
Disease Easier
CNW: February 12, 2008 – DORVAL, QC – For the first time,
Alzheimer’s patients and their caregivers will have the visual
reassurance of continuous delivery of a medication through the
skin. Now there will be no pills to remember, no pills to
swallow, and no worries about medication being taken properly.
The Exelon® patch (rivastigmine), for the symptomatic treatment
of mild to moderate Alzheimer’s disease, is now available in
Canada.
While Alzheimer’s disease is a chronic condition, for which
long-term treatment should be a primary goal, statistics show
that approximately 50% of patients stop treatment with oral
cholinesterase inhibitors (including Exelon®), the group of
drugs typically used to treat the early and middle stage
symptoms of Alzheimer’s disease, after only six months. Some
In the News continued on page 44
43
t"306/%5)&(-0#&t"306/%5)&(-0#&t"306/%5)&(-0#&t"306
In the News continued from page 43
patients simply forget to take their pills, have trouble swallowing
them, or have difficulty with side effects and stop their
medication, which can cancel out any treatment benefits. The
patch optimizes the way the medication is distributed throughout
the body and allows patients to reach and maintain the
maximum effective dose of medication with three times less
reported side effects compared with Exelon® capsules.
The Exelon® patch was designed with compliance in mind, and
preference study results show that the patch was chosen over
Exelon® capsules by more than 70% of Alzheimer’s caregivers
as a method of drug delivery. The patch provides visual
reassurance that medication has been administered, reducing
some of the burden associated with caring for a loved one
affected by Alzheimer’s disease.
Rhode Island Researcher Working on New Kind of Skin
Patch
NewsEdge Corporation: February 1, 2008 – WARWICK,
R.I. – A researcher who helped develop a popular mosquitokilling device now is working on a way to take the sting out of
medical treatments by creating a new skin patch for
administering prescription drugs. Emma Durand was chief
technology officer at American Biophysics Corp. in North
Kingstown, once considered the fastest-growing private
company in the United States. American Biophysics and its
mosquito-sucking yard protector were once toasted by the
national news media and had gained a key retailing ally in
home-improvement goliath Home Depot.
But disputes among American Biophysics investors doomed the
company, which ultimately filed for bankruptcy protection. The
onetime poster child for Rhode Island technology firms was sold
last year to a company in Pennsylvania. The demise of American
Biophysics left Durand with a lot of knowledge about how
human skin works, but no way to apply it. Enlisting the aid of
two partners with experience in polymer manufacturing, Durand
has developed a way to enhance transdermal patches—
medicated adhesive pads that are placed on the skin to deliver
specific doses of medication through the skin and into the
bloodstream.
“Patches really give doctors a degree of control they can’t get
with oral medications,” states Durand, who now heads Isis
Biopolymer Inc., a Warwick startup company she founded this
year. Durand is president and chief technology officer. The twist
Durand and her research team put on the technology is
developing a way to attach medications to a paper-thin, flexible,
printed circuit that monitors and controls dosages. The patches
are 0.002 of an inch thick.
Using computer software, doctors can set the dosages for up to
three medications that are absorbed into a gel on the underside
of the patch. A patient profile would alert the doctor to allergies
or potentially harmful interactions with a person’s active
prescriptions. A doctor would e-mail a prescription to a
44
drugstore, where a pharmacist would transfer the dosing
information via a hand-held control to the wireless patch. Once
programmed, the patches can deliver the medications for up to 7
days before being replaced. Before being discarded, the doctor
can use a wireless scanner to determine how much of the
medication was dispersed into a patient via the patch’s weak
electrical current.
Almost all prescription medications can be put into a form that
can be made into a patch. However, drug patches do have
shortcomings, the NIH notes on its website: the adhesives can
irritate the skin, and the pads can come loose when moistened as
people shower or sweat. Durand and her research team, Michael
Jordan and Miao Yong-Cao, have worked on adhesives that
would reduce those problems.
Dr. Edward Iannuccilli, formerly the chair of Rhode Island
Hospital and currently a professor at Brown Medical School,
recently joined the Isis Board of Directors and its Medical
Advisory Panel. Iannuccilli noted that the multidrug regimens of
elderly patients are difficult for medical professionals to monitor.
“What I liked about Durand’s idea is that there is the quality and
compliance assurance of what she’s doing,” he says. “This is a
way to have safety and compliance.”
Vyteris Announces Redirection of Business to Focus on
Peptide Delivery
Business Wire: February 1, 2008 – FAIR LAWN, N.J. –
Following the successful results of a completed Phase 1 clinical
trial demonstrating that Vyteris’ patented Smart Patch
transdermal technology can deliver a peptide molecule in
humans without the use of needles, Vyteris, with approval from
its Board of Directors, has redirected its business to focus on the
development of peptide delivery using its Smart Patch
technology. The company also states this redirection will allow
for the further development of small molecule delivery using its
technology as well.
Given the significant opportunity within the peptide/small
molecule arena, the company will de-emphasize its marketing
efforts related to its LidoSite product. As a result, the company
will immediately reduce its workforce by approximately 32
employees that were solely or partially dedicated to LidoSite.
“While we continue to believe LidoSite can benefit
venipuncture, dermatology, rheumatology and oncology
practices and improve overall patient experience, we believe
greater opportunities for success for Vyteris exist with
biotechnology companies as well as large pharmaceutical
companies, as they continue to search for new and innovative
ways to improve their product portfolio,” states McIntyre.
JANUARY 2008
Generex Biotechnology Awarded New European Patent
Prime Newswire: January 28, 2008 – WORCESTER, Mass. –
Generex Biotechnology Corporation (NasdaqCM:GNBT –
News) has announced that the European Patent Office has
granted the company a new European patent, “Mixed Micellar
6/%5)&(-0#&t"306/%5)&(-0#&t"306/%5)&(-0#&t"306/%5)
Delivery System and Method of Preparation.’’ The patent will be
validated in 11 European countries, including the United
Kingdom, France, and Germany. The patent contains process and
formulation claims to a pharmaceutical formulation for delivery
through the mucosal membranes.
The company’s flagship product, oral insulin (Generex Orallyn™), which is available for sale in Ecuador for the treatment
of patients with Type-1 and Type-2 diabetes and which was
approved for sale in India in October 2007, is in various stages
of clinical development around the world. For more information,
visit www.generex.com.
Bioadhesive Technology Aids Transmucosal Drug Delivery
in-pharmatechnologist.com: January 28, 2008 – BRIDGEWATER,
N.J. – The Transdermal business group of National Adhesives has
launched the PROLOC™ bioadhesive drug delivery system, a
new bioadhesive technology that provides the means to deliver
drugs locally or systemically from various mucosal absorption
sites on the body. According to National Adhesives officials,
several successful clinical trials have been completed to support
the delivery of drugs across the mucosa using this novel
technology. These clinical trials include successful delivery via
buccal, vaginal, ocular, and nasal absorption sites.
PROLOC™ is a proprietary technology providing superior
bioadhesive properties with the capacity for high drug loading.
The proprietary process, which does not create a new chemical
entity, incorporates a USP-grade polysaccharide and
polycarboxylated polymer and is effective as a sustained or
controlled release preparation with an active agent. The system
is fully erodable and can be utilized as a powder, compressed
into a tablet, or cast as a film.
PROLOC™ is effective for both localized and systemic
therapies. It facilitates transmucosal drug delivery, providing a
convenient means for rapid and direct local or systemic
absorption and onset of therapeutic effects, allowing lower
dosages, and resulting in fewer side effects. More information is
available by contacting [email protected]. N
35th Annual Meeting & Exposition
of the Controlled Release Society
Responding to Global Needs through Delivery Science
*ULYns(ILTON.EW9ORKs.EW9ORK.EW9ORK
Featured Plenary Speakers
Dora Akunyili, National Agency for Food and Drug
Administration and Control, Nigeria
Combating Counterfeit Medicines in Nigeria
Raymond T. Bartus, Ceregene Inc., U.S.A.
The Development of AAV-Neurturin (CERE-120) as a Novel
Neurorestorative Therapy for Advanced Parkinson’s Disease:
From Concept to Clinical Trials and Beyond
Mark E. Davis, California Institute of Technology, U.S.A.
Nanoparticle Cancer Therapeutics: From Concept to Clinic
Rakesh Jain, Massachusetts General Hospital & Harvard
University, U.S.A.
Normalization of Tumor Vasculature and Microenvironment by
Antiangiogenic Therapies: From the Bench to the Bedside and
Back
Thomas Tuschl, Rockefeller University, U.S.A.
Mechanisms of Mammalian Small-RNA-Mediated Gene
Regulation
Jackie Ying, Agency for Science, Technology, and Research,
Singapore
Nanostructure Processing of Advanced Biomaterials and
Biosystems
www.controlledreleasesociety.org/meeting
Calendar of Events
Advances in Tissue Engineering
2008
35th Annual Meeting of the
Controlled Release Society
July 12-16
Hilton New York
New York City, New York U.S.A.
www.controlledreleasesociety.org
MIT: Advances in Controlled Release
Technology: Polymeric Delivery
Systems for Pharmaceuticals, Proteins
and Other Agents
July 21-25
MIT Campus
Cambridge, Massachusetts U.S.A.
http://web.mit.edu/mitpep/pi/courses/
controlled_release_technology.html
CPT2008
July 27-August 1
Québec City Convention Centre
Québec City, Québec, Canada
www.cpt2008.org
August 13-26
Rice University
Houston, Texas U.S.A.
http://tissue.rice.edu/
World Congress of Pharmacy and
Pharmaceutical Sciences 2008
August 29-September 4
Basel, Switzerland
www.fip.org
EUFEPS Workshop Opportunities and
Challenges in Vaccine Delivery
September 15-17
University of Geneva
Site d’Archamps, France
www.eufeps.org/document/_con.
html
NanoDDS ‘08 Nanomedicine and
Drug Delivery Symposium
October 18-19
University of Toronto
Toronto, Canada
www.nanodds.org/template_view.
cfm?PageID=1
Controlled Release Society
3340 Pilot Knob Road
St. Paul, MN 55121
United States of America
2009
The 36th Annual Meeting of the
Controlled Release Society
July 18-22, 2009
Copenhagen, Denmark
www.controlledreleasesociety.org/main/
meetings
World Congress of Pharmacy and
Pharmaceutical Sciences 2009
August 29-September 4
Basel, Switzerland
www.fip.org
2010
The 37th Annual Meeting of the
Controlled Release Society
July 10-14, 2010
Oregon Convention Center
Portland, Oregon U.S.A.
www.controlledreleasesociety.org/main/
meetings
NON-PROFIT ORG.
U.S. POSTAGE
PAID
MINNEAPOLIS, MN
PERMIT NO. 4656